HUT74380A - 7-azabicyclo-[2.2.1]-heptane and -heptene derivatives pharmaceutical compositions containing them, and process for producing former compounds - Google Patents

Description

The present invention relates to 7-azabicyclo [2.2.1] heptane and heptene derivatives of the formula (I) and their salts, and to pharmaceutical compositions containing them, and to processes for their preparation.

To relieve very intense pain, opium derivatives, in particular morphine, are routinely administered to patients. For the relief of mild or moderate pain, analgesics less potent than morphine such as codeine, mixed agonist-antagonist opioid formulations and non-opioid analgesics such as non-steroidal anti-inflammatory drugs (NSAIDS) are administered. Because of the well-known side effects of opium derivatives (which include chemical dependency and respiratory disorders), there is a great need for non-opioid analgesics that are capable of reducing moderate to severe pain with effects that are equal to or better than opioid analgesics. however, the administration of which would not, however, result in serious side effects such as those experienced with opium derivatives. Spande et al., 1992, reported that a high potency analgesic was isolated from the skin of the Ecuadorian Toad Frog, Epipedobates tricolor (Spande et al., J. Am. Chem. Soc. 1992, 114, 3475-3478). The structure of the isolated compound was determined by mass spectroscopy, infrared spectroscopy, and nuclear magnetic resonance, which showed that it was exo-2- (2-chloro-5-pyridyl) -7-azabicyclo [2.2.1] heptane (see Figure 1). . This compound is called epibatidine; it was the first of the naturally occurring 7-azabicyclo [2.2.1] heptanes. The pharmacological studies performed have shown that epibatidine is about 500 times more potent than morphine, based on the results of the Straub tail response; this effect could not be inhibited by the administration of the opium antagonist naloxone. When measured by the hot plate analgesic, epibatidine was found to be about 200 times more potent than morphine. In addition, epibatidine has been found to have negligible affinity for opiate receptors (1/8000 for morphine). Based on the above data, epibatidine appears to be a very potent analgesic with a non-opiate mechanism. Because epibatidine was isolated from the skin of an Ecuadorian poisonous frog, the identification and characterization of this compound did not occur in parallel with its synthesis. The synthesis of 7-azabicyclo [2.2.1] heptane and heptene derivatives (also known as 7-azanorbornane and 7-azanorbornene derivatives) is known to be a difficult process.

In order to obtain a 7-azabicyclo [2.2.1] heptane or -heptene ring system, a two-ring system must be constructed with the appropriately substituted 3-vinylpyridine and a ring + 2 + 4 cycloaddition.

The procedure is illustrated in Scheme A. Pyrrol and its derivatives tend to undergo substitution reactions with dienophiles [Diels, O. and Alder, K., Ann.

1, 498 (1932)], except in one or two cases [Wittig, G., Angew. Chem., 69, 245 (1957)]. The partial aromatic nature of pyrrole and the diene structure of this compound limit the reactivity of this compound and tend to result in more Michael-type addition products (Jones, RA, The Pyrroles, Wiley & Sons, New York, p. 48). (1990)]. In the Diels-Alder reaction between pyrrole derivatives and olefins, Lewis acids [Donnini, G.P.; Just, G.J .: Heterocycl. Chem., 14, 1423 (1977); Bansal, R.C .; McCulloch,

A. W .; Mclnnes, A.G.: Can. J. Chem., 47, 2391 (1969)], the yield can also be increased by increasing the pressure (Kotsuki, H., Móri, Y., Nishizawa, H., Masamitsu, O., Matsuoka, K., Heterocyclic, 19, 1915). (1982); Drew, M.G.B., George, A.V., Isaacs, N.S., Rzepa, H.S. T.C.S. Perkin Trans 1, 1277 (1985)], however, these efforts have yielded limited results. The yield of these reactions is limited by the instability of the 7-azabicyclo [2.2.1] hept-2-ene derivative, and can be reversed by cycloaddition, Mannich reaction or re-aromatization. The limitations of the options are particularly high for compounds requiring the addition of an electron withdrawing group to the resulting olefin [Altenbach, H.J., Martin, H.D., Mayer, B., Muller, M., Vogel,

E .: Chem. Bér. 124, 791 (1991)]. Other methods for the preparation of 7-azanorbornane compounds are disclosed

- 5 Fraser et al., Can. J. Chem., 48, 2065 (1970)], but the multiple step synthetic process and extreme reaction conditions do not allow the synthesis of epibatidine. A summary of the preparation of 7-azanorbornene derivatives can be found in Kricka, L.J., Vernon, J.M. Adv. in Heterocycl. Chem., 16, 87 (1974)].

N-carboalkoxypyrrole is used as a starting material for the preparation of the norbornane derivatives and is reacted with various dienophile derivatives of the acetylene type under the Diels-Alder reaction conditions. However, in neither of the described embodiments is it possible to attach an aromatic or heteroaromatic group to the very important 2-position of the heptane or heptene ring. [Altenbach H.J. et al., Chem. Bér. 124, 791 (1991); Altenbach H.J. et al., Angew. Chem. Int. Ed. Engl. 21 (10), 778 (1992); Gabel N.W .: J. Org. Chem. 27, 301 (1962); Toube T.P .; Pyrroles, Part 2, pp. 92-95. (John Wiley, New York, 1992).

In view of the favorable analgesic properties of epibatidine and the need for potent non-opioid analgesics, it seems appropriate to develop a process for the preparation of a therapeutically active 7-azabicyclo [2.2.1] heptane. and heptene derivatives, or pharmaceutically active derivatives thereof.

yl

The present invention relates to novel 7-azabicyclo [2.2.1] heptane and heptene compounds having analgesic activity.

It is a further object of the present invention to provide a process for the preparation of 7-azabicyclo [2.2.1] heptane and heptene derivatives.

The invention also relates to a novel method of treating pain.

The present invention relates to 7-azabicyclo [2.2.1] heptane and heptene derivatives of formula (I) and pharmaceutically acceptable salts thereof, wherein:

R ¹ and R ⁴ are each independently hydrogen, alkyl, preferably CH ₃ ; I 1 Ih is hydroxy, preferably -CH ₂ OH; alkyloxyalkyl 1, preferably -CH ₂ OCH ₃ ; alkylthioalkyl, preferably -CH ₂ SCH ₃ ; alkylamino, preferably -CH ₂ NH ₂ ; alkylaminoalkyl or alkylamino dialkyl, preferably -CH ₂ NH (CH ₃ ) - and -CH ₂ N (CH ₃ ) ₂ ; alkoxy, preferably -OCH ₃ ; alkoxycarbonyl, preferably methoxycarbonyl; allyl, aryl or thioalkyl, preferably -SCH ₃ ;

R ³ , R ⁵ and R ⁶ are each independently hydrogen, alkyl, preferably -CH ₃ ; an alkyl hydroxy group, preferably -CH ₂ OH; alkyloxyalkyl, preferably -CH ₂ OCH ₃ ; alkylthioalkyl, preferably -CH ₂ SCH ₃ ; alkylamino, preferably -CH ₂ NH ₂ ; alkylaminoalkyl or alkylamino dialkyl, preferably -CH ₂ NH (CH ₃ ) and -CH ₂ N (CH ₃ ) ₂ ; alkoxy, preferably -OCH ₃ ; thioalkyl, preferably -SCH ₃ ; halogen, preferably chlorine or fluorine; haloalkyl, preferably -CF ₃ ; -NH ₂ , alkylamino or dialkylamino, preferably -N (CH ₃ ) 2 and -NHCH ₃ ; cyclic dialkylamino group, preferably

-Ό ^_ O

N N-CH, CH ₂ OH \ ___ / amidine, cyclic amidine group, preferably a

and N-alkyl derivatives thereof;

Η O

II

N-C-alkyl,

-CO ₂ H; CO ₂ -alkyl, preferably -CO ₂ CH ₃ ; -C (O) -alkyl, preferably -C (O) CH ₃ ; -CN, -C (O) NH ₂ , -C (O) NH (alkyl) -, -C (O) N (alkyl) ₂ , preferably -C (O) N (CH ₃ ) ₂ ; allyl, -SO ₂ (alkyl), -SO ₂ (aryl), preferably -SO 2 (C ₆ H ₅ ); -S (O) alkyl, -S (O) aryl, aryl, heteroaryl; or - SO _{2 i}

R ⁵ and R ⁶ together are alkylidene or haloalkylidene, preferably -CH ₂ - and -CF ₂ -; epoxide (-O-), episulfide (-S-), imino [-N (alkyl) - or -N (H) -] or a fused aryl or heteroaryl, preferably a fused phenyl ring;

R ² is independently hydrogen, alkyl, preferably CH ₃ ; alkenyl, preferably -CH ₂ -HC = CH ₂ ; an alkyl hydroxy group, preferably -CH ₂ -OH; alkyloxyalkyl, preferably -CH ₂ -O- (alkyl), alkylamine, preferably -CH ₂ NH ₂ ; carboxylate, C (O) O-alkyl, preferably CO ₂ Me; C (O) O-aryl, C (O) O-heteroaryl, COO-aralkyl, -CN, Q, C (O) Q, alkyl (Q) -, alkenyl (Q), -alkynyl ( Q), -O- (Q), -SQ, -NH-Q or -N (alkyl) -Q;

R ² and R ³ together are -C (O) -N (R ⁸ ) -C (O) or CH (OH) -N (R ⁸ ) -C (O) - wherein R ⁸ is alkyl or aryl preferably phenyl or heteroaryl;

R ⁷ is hydrogen, alkyl, preferably CH ₃ , or -CH ₂ CH ₃ ; alkyl substituted with one or more halogen atoms, preferably -CH ₂ CH ₂ Cl; -CH ₂ - (cycloalkyl) -, preferably -CH ₂ - (cyclopropyl); -CH ₂ CH = CH ₂₁ -CH ₂ CH ₂ (C ₆ H 5), alkyl hydroxy, preferably -CH ₂ CH ₂ OH; alkylamino (alkyl) ₂ , preferably -CH ₂ CH ₂ N (CH ₃ ) ₂ ; dialkyl for alkyloxyalkyl, alkylthioalkyl, aryl, quaternary ammonium, preferably +

N (CH ₃ ) ₂ , N - (R ⁹ ) N - (R ⁹ ) N - (R ⁹ ) N - (R ⁹ ) / \ N II II II

-C-H; C-alkyl; -C-aryl; -C-O- (alkyl);

ss

N- (R ⁹ )

II-C-S- (alkyl);

N- (R ⁹ ) N- (R ⁹ ) ₉ ¹¹

-CNN (R ⁹ ) ₂₎ -C-NHY 'j

I

H is lower alkyl or

ZZ

8II

- (CH ₂ O) oiPR ¹ °; -PR ¹⁰

R ¹¹ R

Z

- (CH ₂ ) NR ⁹ -PR ¹⁰ ·

II - (CH ₂₎ n -SR ₁ ^{to 10;}

II

-CH ₂ OCC (CH ₃ ) ₃ ; -CH ₂ OC-aryl; -CH ₂ OC-alkyl;

wherein R ⁹ is hydrogen or alkyl;

wherein Y 'is CN, NO ₂ , alkyl, OH, -O-alkyl;

wherein Z is oxygen or sulfur;

wherein R ¹⁰ and R ¹¹ are independently -O '-OH, -O-alkyl, -Ο-aryl, -NH ₂ , -NH (alkyl), -N (alkyl) ₂ , -NH (aryl), and

- N (aryl) ₂ , Q represents

H ₃ CN

Cl i

Br

Βγ

wherein the substituent at Q may optionally carry 1 to 3 W substituents, and

W is alkyl, preferably -CH ₃ ; halogen, preferably chlorine or fluorine; aryl, heteroaryl, -OH, alkoxy, preferably -OCH ₃ ; -SH, thioalkyl, preferably -SCH ₃ ; -SO (alkyl), preferably -SOCH ₃ ; -SO ₂ alkyl, preferably -SO ₂ CH ₃ ; -OCH ₂ CH = CH ₂ , -OCH ₂ (C ₆ H ₅ ), CF ₃ , CN, alkylene • · · · · · Ί | ··

- 12-dioxy; preferably -methylenedioxy, -CO ₂ H,

-CO ₂ alkyl, preferably -CO ₂ CH ₃ ; -OCH ₂ CH ₂ OH, -NO ₂ ,

-NH ₂ , -NH (alkyl) -, preferably -NHCH ₃ ; -N (alkyl) ₂ , preferably

-N (CH ₃ ) ₂ ; -NHC (O) alkyl, preferably -NHC (O) CH ₃ ; -SO ₂ CF ₃ , or -NHCH ₂ aryl, preferably -NHCH ₂ (C ₆ H ₅ ); and wherein the dashed line represents an optional double bond.

The compounds of the present invention exhibit central and peripheral analgesic activity, or alternatively have anti-inflammatory activity and, as such, can be used to treat pain and reduce inflammation in mammals, including human patients.

The present invention also provides a method of treating pain comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, or a mixture thereof, to a patient in need of analgesic treatment, wherein the active ingredient is preferably admixed with pharmaceutically acceptable excipients.

The present invention also relates to a process for the preparation of the 7-azabicyclo [2.2.1] heptane and heptene derivatives of the invention. In one embodiment, the active compounds, or precursors thereof, of the present invention are prepared by reacting complexes of pentaamine-osmium (II) with pyrrole with dipolarophilic compounds such as 3-vinylpyridine derivatives. Alternatively, the active compounds of the present invention and their precursors may be prepared by providing N- (electron withdrawing substituent) pyrrole with an arylsulfonyl (optionally substituted with aryl, alkyl, heterocyclic or heteroaryl). with an acetylene derivative under the conditions of the Diels-Alder reaction.

Figure 1 shows the chemical structure of exo-2- (2-chloro-5-pyridyl) -7-azabicyclo [2.2.1] heptane (epibatidine).

2a. and 2b. Figures 1 to 5 illustrate the preparation of the active ingredient by reacting an N- (electron withdrawing substituent) pyrrole derivative with an arylsulfonyl (optionally substituted with aryl or heteroaryl) acetylene under the conditions of the Diels-Alder reaction.

I. Definitions

The term alkyl as used herein is linear, branched, or cyclic (or combinations thereof).

Refers to hydrocarbons having from 1 to 10 carbon atoms, of which methyl, ethyl, propyl, isopropyl, cyclopropylmethyl, cyclobutylmethyl, butyl, isobutyl, tert-butyl, pentyl, cyclopentyl are mentioned as examples. -, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethyl-butyl, 2,3-dimethyl-butyl, heptyl, octyl, nonyl- and decyl groups.

The term lower alkyl, as used herein, refers to saturated hydrocarbon radicals having from 1 to 6 carbon atoms in the chain, branched or cyclic (in this case, the radicals having 5 to 6 carbon atoms), including, but not limited to, and methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclopropylmethyl, pentyl, cyclopentyl, cyclobutylmethyl, isopentyl, neopentyl, hexyl, isohexyl, cyclohexyl, 3-methylpentyl, 2,2-dimethylbutyl and 2,3-dimethylbutyl.

The term alkylamino refers to an amino group having an alkyl substituent.

The term alkynyl means a straight or branched hydrocarbon group having from 2 to 10 carbon atoms and having at least one triple bond.

Lower alkynyl refers to C2-C6 alkynyl groups, such as acetylenyl and propynyl.

The term aryl as used herein refers to phenyl or substituted phenyl, wherein the substituent may be halogen, alkyl, alkoxy, alkylthio, haloalkyl, hydroxyalkyl, alkoxyalkyl, methylenedioxy, cyano, C (O) - (lower alkyl), carboxyl, CO ₂ alkyl, amide, amino, alkylamino and dialkylamino, and wherein the aryl group may have from 1 to 3 substituents.

The term halogen means fluorine, chlorine, bromine and iodine.

The term aralkyl refers to an aryl group having an alkyl substituent.

The term "alkaryl" refers to an alkyl group having an aryl substituent, including, but not limited to, benzyl, substituted benzyl, phenethyl, or substituted. · I

a phenethyl group, which may be substituted with those listed in that chapter.

The term heteroaryl or heteroaromatic group as used herein refers to an aromatic group containing at least one sulfur atom, oxygen atom or nitrogen atom in the aromatic ring. Examples include, but are not limited to, furyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indole. , isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, , cinnolinyl, phthalazinyl, quinoxalinyl, xanthynyl, hypoxanthinyl, pteridinyl, 5-azacitidinyl, 5-azauracyl, triazolopyridinyl, imidazolo-pyridinyl, pyrrolo-pyrimidinyl and pyrazolo-pyrimidinyl.

The term organic or inorganic anion refers to an organic or inorganic group which carries a negative charge and which may form a negative portion of a salt.

The term "pharmaceutically acceptable use" refers to an organic or inorganic moiety which carries a positive charge and which may form a salt with a pharmaceutically active agent.

The term enantiomerically enriched compound or composition refers to a compound or composition that contains at least 95% by weight of one of the enantiomers of the compound.

The term pharmacologically active derivative refers to a compound which, when administered to a patient, is capable of delivering, directly or indirectly, the active ingredient of the invention.

As used herein, a dipolarophilic compound refers to a group or compound that reacts with a dipolar compound to form a cycloaddition product.

The term dienophilic derivative as used herein refers to a group or compound that reacts with a diene to form a cycloaddition product.

The term η as used herein refers to a metal complex at the level of the pi electron shell of an unsaturated compound, the index after η being the number of sp ² carbon atoms bound to the metal.

As used herein, the term electron-withdrawing substituent refers to a substituent which, by induction or resonance, attracts electron density from the group to which it is attached. Numerous electron withdrawing substituents are known to those skilled in the art of organic synthesis.

II. Active Ingredients

The 7-azabicyclo [2.2.1] heptane and heptene derivatives of formula (I) exhibit central and peripheral analgesic activity and anti-inflammatory activity and are therefore useful in the treatment of pain and inflammation in mammals, including humans. The present invention also provides a method of treating pain comprising administering an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or derivative thereof, or a mixture thereof, for analgesic treatment. for patients in need, preferably in admixture with pharmaceutically acceptable excipients and carriers.

The numbering of the 7-azabicyclo [2.2.1] heptane and heptene derivatives is illustrated below:

7-Azabicyclo [2.2.1] heptane and heptene derivatives can have a wide variety of stereochemical configurations. As described above, the compounds of the present invention are prepared by reacting a dienophile derivative with pyrrole derivatives by a Diels-Alder cycloaddition reaction, or by modifying the Diels-Alder reaction by preparing a dipolarophilic compound, pentaamine osmium ( II) with an activated pyrrole derivative. In the transition state of the cycloaddition reaction, the diene or dienophilic compounds have two possible three-dimensional structures «« · 4 «· <« ···· · · · · · · · «

- 18 (orientation), referred to as endo or exo. An endo configuration is formed when unsaturated groups in dienophile (or dipolarophile) are located close to the diene double bond. An exo configuration is formed when unsaturated groups in dienophile (or dipolarophile) are located away from the double bond formed in diene. Depending on the substitution of the carbon atoms, compounds of the endo and exo configurations can form a number of stereoisomers.

The 2, 3, 5 and 6 carbon atoms in the 7-azabicyclo [2.2.1] heptane derivatives and the 2 and 3 or 5 and 6 carbon atoms in the 7-azabicyclo [2.2.1] heptene give an optically active compound. when different substituents are attached to these carbon atoms. When at least one carbon atom in the molecule is chiral (capable of forming an optically active compound), the asymmetrically substituted bicyclic compounds are formed in the form of one or more diastereomeric pairs. The R groups in the compounds of formula I may also contain chiral carbon atoms and, consequently, optically active centers.

It is often the case that one or the other enantiomer exhibits a more potent effect on one biologically active compound and may be less toxic than another enantiomer of the same compound. In such cases, it is preferable that the compound enriched in this enantiomer be a · «* * 44 • 44 44 44 44 44

- 19 for medical treatment of human or other patients.

It is known to one skilled in the art how to isolate the enantiomers of the active compounds by known methods and then to evaluate the biological activity of the isolated enantiomers by known methods or methods described herein.

The enrichment of the optically active component in the test compound can be determined using NMR shift chiral reagents, polarimetric method or chiral HPLC.

The classic methods of resolution include various physical and chemical solutions. For example, since it is present in the compounds of the invention are basic amines (N ^7), the compound may be reacted with a chiral acid can be prepared by diastereoisomeric salts, wherein solubility of each salt may be substantially different. Examples include, but are not limited to, malic acid, mandelic acid, dibenzoyl tartaric acid, 3-bromo-camphor-B-sulfonic acid, 10-camphorsulfonic acid, and di-p-toluoyl-tartaric acid and chloroformic acid. (-) - menthyl ester. Similarly, a free amine or hydroxyl group in a compound can be reacted with a chiral acid to form diastereomeric amides or esters, which have substantially different physical properties, thereby allowing diastereomers to be isolated. The enantiomerically pure or at least enriched compounds can also be prepared by treating the racemic mixture with a cr

9 k · ··· · il

Passing through 20 matrographic columns designed for chiral separation, including cyclodextrin-containing columns (manufactured by Rainin Corporation).

Examples of the compounds of the present invention include, but are not limited to, the following.

(A) Epibatidine isomers:

1- 7-aza-2-exo (2-chloro-5-pyridyl) bicyclo [2.2.1] heptane and pharmaceutically acceptable salts thereof, including the hydrochloride salt; 1-7-aza-2-exo (2-chloro-5-pyridyl) bicyclo [2.2.1] heptane and pharmaceutically acceptable salts thereof, such as the hydrochloride salt;

d and ε-7-aza-endo- (2-chloro-5-pyridyl) -bicyclo [2.2.1] heptane and pharmaceutically acceptable salts thereof, such as the hydrochloride salt;

(B) D-and I-enantiomers of 7-azabicyclo [2.2.1] heptane derivatives which may have the following substituents:

7-methyl, 7-allyl, 7-cyclopropylmethyl, 7-cyclobutylmethyl, 7-phenethyl, 7-hydroxyethyl, 7-methoxyethyl, 7-methylthio ethyl, 7-dimethylaminopropyl, 7-formamidinyl, 7- (2-chloroethyl), 7-disodium phosphate, and 7- (4-methoxybenzyl) substituents.

A combination of a 2-exo (2-chloro-5-pyridyl) substituent;

the above 7-methyl, 7-allyl, 7-cyclopropylmethyl, 7-cyclobutylmethyl, 7-phenethyl, 7-hydroxyethyl, 7-methoxyethyl, 7-methylthio ethyl, 7-dimethylaminopropyl, 7-formamidinyl, 7- (2-chloroethyl), 7-disodium phosphate and 7- (4-methoxybenzyl) substituents may also be combined with the following: :

·· ·· ·· - * • · · * · * ··· »· ··« 4 • · «ιί

2-exo- (3-pyridyl); 2-endo- (3-pyridyl); 7-methyl-2-exo- (3-pyridyl); 7-cyclopropylmethyl-2-exo- (3-pyridyl); 7-phenethyl-2-exo- (3-pyridyl);

2-exo- (4-pyridyl), 7-methyl-2-exo- (4-pyridyl); 7-allyl-2-exo- (4-pyridyl); 7-cyclopropylmethyl-2-exo- (4-pyridyl);

2-exo (3-chloro-4-pyridyl); 7-cyclopropylmethyl-2-exo- (3-chloro-4-pyridyl); 7-phenethyl-2-exo- (3-chloro-4-pyridyl); 2-exo- (2-chloro-3-pyridyl); 2-exo- (2-chloro-4-pyridyl);

2-exo- (2-fluoro-5-pyridyl); 2-exo- (2-methoxy-5-pyridyl); 2-exo (2-methylthio-5-pyridyl); 2-exo- (2-methyl 1-5-pyridyl); 2-exo- (2-dimethylamino-5-pyridyl); 2-exo- (2-hydroxy-5-pyridyl) and its 7-cyclo-propyl methyl derivatives;

Also mentioned are the exo and endo isomers of the following substituents:

2-phenyl, 2- (3-chlorophenyl) -;

2- (3-dimethylamino-phenyl) -; 2- (3-trifluoromethyl-phenyl) -;

2- (3,4-methylenedioxy-phenyl) -; 2- (3,4-dimethoxyphenyl) -; 2- (4-fluorophenyl) -;

2- (4-hydroxyphenyl) -; 2- (4-methylsulfanyl-phenyl) -;

2- (4-methylsulfonylphenyl) -, 2- (3,5-difluorophenyl) -; 2- (2-chlorophenyl) -;

2- (2-naphthyl) -; 2- (7-methoxy-2-naphthyl) -;

2- (5-chloro-2-thienyl) -; 2- (chloro-5-thiazolyl) -; 2- (4-pyrimidyl) -; 2- (2-chloro-5-pyrimidyl) -; 2- (5-chloro-2-pyridazinyl) -; 2- (1,2,5-thiadiazol-3-yl) -; 2- (5-dimethylaminomethyl-2-furanyl) -; 2- (5-indolyl) -;

«44 · ·· 44 · · * ···· # • ·· · · * 44 4» * * · ♦ • · · 4 · · η

- 22 2- (5-fluoro-3-indolyl) -; 2- (5-methoxy-3-indolyl) -; 2- (4-chloro-benzyl) -; 2- (5-chloro-3-pyridyl 1-methyl) -; 2- (4-pyridylmethyl) -; 2 nikotinil-; 2- (6-chloro-nicotinyl) -; 2-ison i cot i n i I-; 2- (3-chloro-isonicotinyl) -; 2- (4-chlorobenzoyl) -; 2- (4-dimethylamino-benzoyl) -; 2- (3,4-dimethoxybenzoyl) and their 7-methyl, 7-cyclopropylmethyl, 7-allyl and 7-phenethyl derivatives.

(C) Exo and endo isomers of 7-aza-2- (2-chloro-5-pyridyl) -bicyclo [2.2.1] heptane having the following substituents at positions 1, 2, 3, 4, 5 or 6 :

1- or 4-methyl; 1- or 4-hydroxymethyl; 1- or 4-methoxymethyl; 1- or 4-carbonylmethoxy; 1- or 4-allyl; 1 or 4-benzyl; 1- or 4- (4-fluorobenzyl); 1- or 4- (4-methoxybenzyl); 1,4-dimethyl; 1,4-bis (hydroxymethyl); 1,4-bis (methoxymethyl); 1,6- or 4,5-butylidene;

Endo or exo-3-methyl; 3-hydroxymethyl; 3-methoxymethyl;

3-methoxy-carbonyl; 3-carboxy; 3-carbamoyl; 3-cyano; 3-acetyl; 3-aminomethyl; 3-dimethyl-amino-methyl; 3-methyl-thio-methyl; 3-phenylsulfonyl; 3-methanesulfonyl; 3-benzyl; 3-allyl,

3-cyano-1,4-dimethyl-; 3-hydroxymethyl-1,4-dimethyl-; 3-methoxymethyl-1,4-dimethyl-; 3-methylthiomethyl-1, 1,4-dimethyl-; 5,6-bis (trifluoromethyl) -; 5- or 6-methoxy; 5 or 6-methyl; 5,6-dimethyl-; Methoxy-5,6-dicarbonyl; 5,6-bis (hydroxymethyl) -; 5,6-bis (methoxymethyl) -; 5 or 6-chloro; 5 or 6-hydroxy; 5,6-dehydro-, 5,6-dehydro-1,4-dimethyl-; 3,3-dimethyl-; 2-methyl-; 2,3-dimethyl-; 5,6-methylene;

and their corresponding 7-methyl, 7-cyclopropylmethyl, 7-allyl, 7-phenethyl and 7- (4-fluorobenzyl) derivatives.

(D) 7-Aza-2- (2-chloro-4-pyridyl) bicyclo [2.2.1] hept-2-ene and its 7-methyl, 7-allyl, 7-cyclopropyl methyl, 7-phenethyl and 7- (4-methoxyphenethyl) derivatives; and the corresponding 1,4-dimethyl; 1- or 4-methyl; 5,6-dimethyl and 5,6-bis (trifluoromethyl) analogues.

(E) benzo [5a, 6a] epibatidine and an N-methyl derivative thereof;

2,3-dehidroepibatidin; 5,6-bis (trifluoromethyl) -dezklórepibatidin; Carbonyl-2-methoxy-7-methyl-7-azabicyclo [2.2.1] heptane; 2-cyano-7-methyl-7-azabicyclo [2.2.1] heptane; trans-2,3-bis-methoxy-carbonyl-7-azabicyclo [2.2.1] heptane; exo-2-amino-7-methyl-7-azabicyclo [2.2.1] heptane; exo-2- (1-pyridylmethyl) -7-methyl-7-azabicyclo [2.2.1] heptane; exo-2-hydroxymethyl-7-methyl-7-azabicyclo [2.2.1] heptane; exo-2-hydroxymethyl-7-methyl-2-azabicyclo [2.2.1] heptane.

III. Methods for the preparation of optionally substituted 7-azabicyclo [2.2.1] heptane and heptene derivatives

A. Preparation of the 7-azabicyclo [2.2.1] heptane or heptene ring system starting from pyrrole through the pentaamine-osmium (II) complex

Surprisingly, it has been found that 7-azabicyclo [2.2.1] heptane and heptene derivatives can be prepared by reacting a dipolarophilic compound with an optionally substituted pyrrole derivative wherein the pyrrole derivative is pentaamine osmium (II). forms a complex.

Any dipolarophilic compound which is capable of using the pentaamine-osmium-pyrrole complex can be used in this reaction.

.. · <. · .. · to give optionally substituted 7-azabicyclo [2.2.1] heptene which can be converted to the corresponding 7-azabicyclo [2.2.1] heptane. Examples of dipolarophiles derivatives include the compounds of Zi-C = CZ _2, wherein in the formula, and Z ₂ are each independently an electron acceptor group; these include, but are not limited to, esters, nitrile, ketone, aldehyde, amide, -NO ₂ , sulfone, anhydride, -CF ₃ , pyridinium salts, and, for example, CO (alkyl, aryl) - or heteroaryl, C (O) H, CO ₂ (alkyl, aryl or heteroaryl), SO ₂ (alkyl, aryl or heteroaryl); in addition, Z ₁ and Z _{2 may} together be (CO) ₂ O or (CO) ₂ N. Suitable compounds include N-methylated and 6-carboxylated pyridyl acrylates, alkyl acrylates, alkyl methacrylates, pyridyl substituted vinyl sulfones, acrylonitriles, anhydrides, maleic acid imides, alpha-methylene-butyrolactone, fumarate.

Similarly, it can be used from any optionally substituted red that is capable of reacting with a dipolarophilic compound to form a complex with pentaamine-osmium (II). Suitable pyrrole derivatives include 2,5-dialkylpyrrole, 2-alkyl 1-pyrrole, 3-alkylpyrrole, 1-alkyl 1-pyrrole, 3,4-dialkylpyrrole, pyrrole, 1-silylated pyrrole, (1, 2 or 3) -alkoxy or aminopyrrole, 2,3-dialkoxypyrrole, 2,5-dialkoxypyrrole and 3,4-dialkoxypyrrole.

·· «R • * · • ··· 4

Scheme 1 shows that it is capable of complexing on red with the η-based pentaamine osmium (II) in which osmium coordinates the heterocyclic group through C ² and C ³ . At 20 ° C, this compound is in equilibrium with the isomer to which the metal is bound through C ³ . Although the 3,4-η structure is only a minor component (4G _iZ0 > 3 kcal / mol), the metal coordination in this structure converts the remainder of the red into an azomethine ylide structure (R ² C ⁺ -N (R) -CR ² <-> R ² C = N ⁺ (R) -C'R ² ), thus the ligand exhibits a greatly increased tendency to enter the 1,3-dipolar cycloaddition with the corresponding dipolarophilic compound.

Reaction 1

Dipolar cycloaddition of a complex η ² -ρΪΓΓθΙ made with a dipolarophile

Os (II) = [Os (NH ₃ ) b] (OTf) ₂

The resulting 7-azabicyclo [2.2.1] hept-5-ene ligand is unstable with respect to ring remodeling, but coordination with the metal greatly stabilizes the complex and thus it is possible that while the structure of the two rings remains unchanged , make modifications to the functional groups. For example, in the norbornene basic structure, electron-withdrawing groups can be introduced at the 2 or 3 position by known methods to produce 7-azanorbornene derivatives bearing various groups. Thus, for example, as shown in Scheme 2, the exocarbonyl cycloadduct complex of formula (2), starting from 2,5-dimethylpyrrole. . · *. ··: · ··· · ···.

.. ·;

The reaction mixture is prepared in a single reaction vessel without isolation of the intermediate, reduced to the corresponding alcohol or cleaved by oxidation to afford the relatively inaccessible 5-hydroxymethyl-7-azanorbornene (3).

Reaction 2

5-substituted-7-azanorbornene (Os (II) = [Os (NH ₃ ) _e ] (Otf) ₂ ); DMAc = Ν, Ν-dimethylacetamide; Otf = CF3SO3

This reaction is carried out in the case of dipolarophil

Using 3-vinylpyridine, the epibatidine ring system is constructed. In the case where methyl trans-3- (3-pyridyl) acrylate is used as starting material in the above reaction sequence (using 2,5-dimethylpyrrole complex for this step, see Scheme 2), (4) which has the carbon backbone of the natural compound.

In epibatidine, there is no substituent on the carbon atoms (C ¹ and C ⁴ ) at the bridgehead. The reactivity of the simple pentaamine-osmium (II) -pyrrole complexes against the dipolarophiles is reduced in the following order: 2,5-dimethylpyrrole>N-methylpyrrole> from pyrid.

In general, dipolarophiles can be activated if the electron-withdrawing group attached to the olefin is appropriately selected, or high pressure is used to produce the cycloadduct when no substituent is present on the carbon at the bridgehead. Although the starting pyrrole complex is a complex mixture, the N-methylpyrrole is N-methylated and 6-carboxylated. ₉ il

- Reacts with 27 pyridyl acrylates to form the cycloadduct 5 and 6 in the form of a single diastereomer.

Alternatively, the azabicyclo [2.2.1] heptane ring may be stabilized by protonation of the secondary amine (and pyridyl group) followed by oxidation to remove the metal and hydrogenation of the azanorbornene in situ. This method is illustrated in Scheme 3, which illustrates the preparation of 1,4-dimethyl-exocarbonylmethoxychloro-epibatidine (7).

Reaction 3

Preparation of 7-Azanorbornane by Complex Degradation and Hydrogenation ([Os] ²⁺ = [Os (NH ₃ ) ₆ ] (Otf) ₂ )

The preparation of the optionally substituted 7-azabicyclo [2.2.1] heptanes and 7-azabicyclo [2.2.1] hept-5-ene via pentaamine-osmium (II) complexes takes place in three steps. In the first step, the optionally substituted pyrrole compound is treated with pentaamine osmium (II). It is preferred that the pyrrole complex be used in excess. Pentaamine osmium (II) is generally prepared in situ by reduction of pentaamine osmium (II). An electron reducing agent having a reducing potential of less than -0.75 V hydrogen is used. In addition to pentaamine osmium (II), any anion may be used as counterion which does not adversely affect the course of the reaction. Typically, the anion may be CF ₃ SO ₃ ', (Otf), PF ₆ , X' or (alkyl or aryl) SO ₃ '.

yl

Any chemical or electrochemical reducing agent that does not cause side reactions or does not participate in an unwanted side reaction can be used to reduce the osmium complex from the III state to the II state. Suitable reducing agents include magnesium, zinc, aluminum, sodium, cobaltocene and electrochemical reduction. According to a preferred embodiment of the invention, an activated magnesium powder is used.

The mixture of the optionally substituted red pentaamine-osmium (III) and the reducing agent is stirred at a temperature of 0 ° C to 50 ° C until the formation of the desired organic metal complex is complete, usually from 0.1 to 1.0 hour. . The reaction may be carried out in a polar or non-polar solvent, including, but not limited to, NN-dimethylacetamide, N, N-dimethylformamide, water, methanol, acetonitrile, acetone, dimethylsulfoxide, CH ₂ Cl ₂ , and the like. dimethoxyethane. The reaction is carried out with the exclusion of oxygen, usually under a nitrogen atmosphere, at a pressure of 1 atmosphere or more.

In the second step of the process, the dipolarophilic compound is added from the red to the solution containing the pentaamine-osmium (II) complex from the red to give an optionally substituted 7-azabicyclo [2.2.1] hept-5-ene. The molar ratio of dipolarophile to pyrrole in the reaction may be arbitrary, provided that the desired end product is obtained. Generally, by selecting the molar ratio of dipolarophil to red from 1 to 10, the product can be obtained in an appropriate yield. The reaction mixture is stirred at a temperature of from 10 to 50 ° C until product formation is complete, generally the reaction time is from 1 to 24 hours.

'Τ'

After the formation of the two ring systems, an additional step, if desired, is introduced while the pentaamine osmium is still complexed with the pi-electron path of the heptane group, whereby functional groups can be applied to the compound containing the two rings. For example, by reduction, esters can be converted to alcohols, nitriles to amines, sulfones to sulfides, nitro groups to amine groups, and amide groups to amine groups. By using the Barton decarboxylation method, sulfone and carboxylate derivatives can be reductively removed. When introducing functional groups, high temperatures and strong bases should be avoided to prevent unwanted side reactions in the ring.

In the third step, the pentaamine-osmium (II) complex is removed from the optionally substituted 7-azabicyclo [2.2.1] hept-5-ene by, for example, cerium (IV) or oxygen in an acidic solution. For example, 7-azabicyclo [2.2.1] hept-5-ene may be treated with an equivalent amount of a cerium reagent at 20 ° C in a polar solvent such as acetonitrile. Suitable reagents include Ce (NO ₃ ) 6 (NH ₄ ) 2, DDQ, or other inorganic or organic oxidizing agents having an E value of greater than + 0.70 volts hydrogen. Alternatively, the osmium reagent is removed by subjecting the complex to a heat treatment, generally from about 50 ° C to about 100 ° C.

Proceeding as described above, a number of substituted 7-azanorbornane and 7-azanorbornene derivatives can be prepared. Examples of the compounds prepared include those listed in Tables 1 and 2.

Some of the compounds listed herein may be used as intermediates for the preparation of target compounds having heteroaryl or polar substituents such as R ² and / or R ³ .

Table 1

R. r ₂ r ₃ 7-Azabicyclo [2.2.1] heptane H exo-CH ₂ OH H H O-CH ₂ OH ₃ H H ασ-CHjOH enJo-3-ρ * H exo-CO ₂ CH 3 endo-3-ρι H exo-COjCHj ero-3-pyridinyl H eio-SO ₂ Ph enJo-3-ρ < H INZ / o SOjPh exo-3-pyridinyl 7-azabicyclo | chloride [2.2.1] hept-5-ene. H dxo-CH ₂ OH H CBZ eio-CH ₂ OH H CBZ «oOCBz H H O-CH ₂ OH endo-3-ρι

Table 2

Example

15 CH? exo-COOMe H 15 CH? endo-COOMe H 16 CH? exo C-N H 16 CH ₃ Endo-C = N H 17 H exo-COOMe endo-COOMe 18 H exo- -C (O) -N (Ph) -C (O) - 18 H endo- -C (O) -N (Ph) -C (O) - 19 et exo- -C (O) -N (Ph) -C (O) - 20 H exo- -C (O) -N (Ph) -C (O) - 21 CH? exo-CHjNHj H 22 CH exo-CH ₂ NC «H4 H 23 CH? exo-CH ₂ OH H 24 CH? exo-CH ₂ OOCPh H

The preparation of the compounds of formula (I) via the 5,6-r] ² -7-azabicyclo [2.2.1] hept-5-ene is illustrated below. The examples presented are for illustrative purposes only and are not intended to be limiting.

Example 1

Preparation of 1,4-Di-methyl-2-exo- (hydroxymethyl) -7-azabicyclo [2.2.1] hept-5-ene (8)

727 mg (1.0 mmol) of (8) the compound 5,6-T] ² -ozmium complex dissolved in 2 g of acetonitrile, and the solution was acidified with excess triflic acid (250 mg, 1.67 mmol) and stir at -10 ° C Treat with 560 mg (1.02 mmol) of cerium ammonium nitrate and 560 mg (3.73 mmol) of triflinic acid, also at -10 ° C, in 2 g of acetonitrile. 1-2 ml of water are added to dissolve the precipitating salts, and the mixture is made basic with 40 ml of 10% aqueous sodium carboxylate, and the product is then made up to 20 ml with methylene chloride. Extract five times. The extract was dried over MgSO ₄ and the solvent was evaporated to give 147 mg of a brown oil. The crude product obtained was purified by column chromatography using silica gel and methanol / methylene chloride (1:10) containing 15% by weight of ammonia; 62 mg (41%) of pure 8 are obtained as an oil (Rf = 0.5).

¹ H-NMR (300 MHz, CDCl ₃ ) δ 6.31 (d, J = 5.3 Hz, 1H), 6.09 (d, J = 5.3 Hz, 1H), 3.99 (dd, J = 10.3, 2.1 Hz, 1H), 3.67 (dd, J = 10.3, 2.1, 1H), 3.6-2.8 (broad v, ~ 2H, OH and NH).

1.4-1.8 (m, 3H); 1.48 (s, 3H); 1.47 (s, 3H).

¹³ C-NMR (75 MHz, CDCl ₃ ): d 145.2 (CH), 141.5 (CH), 69.9 (C), 67.0 (C), 61.5 (CH ₂ ), 41 , 7 (CH), 37.0 (CH ₂ ), 18.9 (CH ₃ ), 15.7 (CH ₃ ).

The product was converted to the citrate salt, m.p. 186-188 ° C.

Elemental analysis based on the formula ΰ ₁₅ Ηι ₈ Ν ₄ Ο ₈ :

Calculated: C, 47.12; H, 4.75; N, 14.65;

Found: C, 46.96; H, 4.52; N, 14.66.

Example 2

N-CBZ-1,4-Dimethyl-2-exo- (hydroxymethyl) -7-azabicyclo [2.2.1] hept-5-ene (9) and N, O-bis (CBZ) -1,4 -dimethyl-2

Preparation of -exo- (hydroxymethyl) -7-azabicyclo [2.2.1] hept-5-ene (10)

1.0 mmol of the crude amino alcohol 8 obtained from the osmium complex (prepared as described in the previous example) is suspended in an aqueous sodium carbonate solution (containing 0.38 g of Na ₂ CO ₃ in 2 g of water); and the resulting mixture was cooled to 0 ° C. 510 mg (3 mmol) of benzyl chloroformate was added and the mixture was allowed to warm to room temperature with vigorous stirring. After 20 hours at 25 ° C, the mixture was extracted with methylene chloride, and the extracts were combined and concentrated on a rotary evaporator to give 0.4 g of a brown oil. The crude product was purified by chromatography using ethyl acetate / petroleum ether (1: 8) and the procedure repeated; 43 mg (10%) of product 9 and 64 mg (22%) of product 10 (Rf = 0.5 and 0.1) are obtained; test results of compound 9: 'H NMR (300 MHz, _CDCl3) d 7.32 (m, 5H, phenyl), 6.06 (AB q, J = 5.7 Hz, 2H, H5 and H6) , 5.04 (s, 2H, OCH ₂ Ph); 3.69 (m, 2H, _CH2 0H);

2.18 (bs, 1H, OH), 1.75 (2Xs, 6H, CH ₃ ), 1.7 (m, overlap, 1H), 1.55 (m, 2H); ¹³ C NMR (75 MHz, CDCl ₃ ): δ 155.2 (CO),

140.5 (CH, C5 or C6), 140.2 (CH, C6 or C5), 136.4 (C, ipso), 128.3 (CH), 127.9 (CH), 127.8 (CH ), 71.1 (C), 69.0 (C),

66.4 (CH ₂ OH), 63.0 (CH ₂ ), 45.6 (CH), 37.7 (CH ₂ ), 19.4 (CH ₃ ),

16.8 (CH ₃ ).

Compound 10: 1 H-NMR (300 MHz, CDCl ₃ ) δ 7.37 (m, 5H, phenyl), 7.32 (m, 5H, phenyl); 6.07 (Abq, J = 5.5 Hz, 2H, H5 and H6), 5.16 (s, 2H, _OCH2 Ph), 5.05 (ABq, J = 13.5 Hz, 2H), OCH ₂ Ph), 4.33 (dd, J = 10.5, 7 Hz, 1H, 1/2 CH ₂ OCBZ), 4.06 (dd, J = 10.5, 7.5 Hz, 1H, 1 / 2 CH ₂ OCBZ), 1.94 (m, 1H, H 2), 1.79 (s, 3H, CH ₃ ), 1.75 (s, 3H, CH ₃ ), 1.60 (dd, J = 11 , 4.9 Hz, 1H, H3 _e ndo), 1.4 (dd, J = 11.4,

3.6 Hz, H3 _eX0 ). ¹³ C NMR (75 MHz, CDCl ₃ ): δ 155.0 (CO), 154.9 (CO), 140.5 (CH, C5 or C6), 140.5 (CH, C6 or C5), 136 , 4 (C, ipso), 135.2 (C, ipso), 128.5 (overlap 2 X CH), 128.4 (CH), 128.3 (CH), 128.0 (CH), 127, Δ (CH), 70.8 (C), 69.6 (overlap 2X CH ₂ ), 68.9 (C), 66.3 (CH ₂ O), 43.2 (CH, C 5), 38.7 (CH ₂ , C 6), 19.3 (CH ₃ ), 17.0 (CH ₃ ).

yl

Example 3

Preparation of 1,4-dimethyl-2-endo- (3'-pyridyl) -3-exo- (hydroxymethyl) -7-azabicyclo [2.2.1] hept-5-ene (11)

Starting material 5.6 r ^{The 2-} osmium complex was used and treated as described for the preparation of Compound 8.

¹ H-NMR: 6.43 (d, J = 6Hz, 1H, H5 or H6), 6.0 (d, J = 6Hz, 1H, H6 or H5), 4.0 (dd, J = 10 , 2.5 Hz, 1H, 1/2 CH ₂ OH),

3.75 (dd, J = 10, 2.5 Hz, 1/2 CH ₂ OH), 1.55 (s, CH ₃ ), 1.38 (s, CH ₃ ).

Example 4

Preparation of 1,4-Di-methyl-2-exo- (hydroxymethyl) -7-azabicyclo [2.2.1] heptane (12) mg of crude product (8) (0.56 mmol) 30 mg of 10% activated carbon palladium and 0.5 g of methanol were hydrogenated in a 5 ml round bottom flask at 1 atmosphere for 30 minutes. The reaction mixture was filtered through Celite and concentrated to give 78 mg of an oily product. The resulting material was purified by thin layer chromatography (0.25 mm, 20 x 20 cm; eluent: methanolic NH ₃ / CH ₂ Cl _{2 =} 1: 6) to afford 14 mg (16%) of pure 12 (R f = 0). 5).

1 H-NMR (300 MHz, CDCl ₃ ) δ 3.89 (broad, 2H, NH and OH),

3.82 (d J = 10.6 Hz, 1/2 CH ₂ OH), 3.38 (d, J = 10.6 Hz, 1/2 CH ₂ OH), 1.7-1.5 (m , 7H, 3 x CH ₂ + CH); 1.41 (s, 3H, CH ₃ ); 1.37 (s, 3H, CH ₃ );

¹³ C-NMR (75 MHz, CDCl ₃ ): d 66.8, 64.0, 63.8, 45.5, 40.0, 39.1, 39.07, 20.6, 17.8.

Example 5

Preparation of 1,4-Di-methyl-2-exo-carboxymethyl-7-azabicyclo [2.2.1] heptane (13)

The title compound was prepared as described for compound 8, the corresponding 2,3-f] -ozmium ² complex (18) is used as a starting material, this compound is protonated and cleaved by Ce (IV) complex. The acetonitrile solution was concentrated and the resulting unstable protonated 7-azanorbornene was hydrogenated in methanol as described for 12. Compound 13 is obtained in the form of an oily product after aqueous work-up (see Preparation of Compound 8) and the crude product is purified by thin layer chromatography.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.60 (s, 3H, CH ₃ O); 2.63 (dd, J = 8.1, 5.1 Hz, 1H, H2), 2.49 (broad s, 1H, NH), 1.82 (dd, J = 12.2, 8.1 Hz) , 1H, H3 _endo), 1.75-1.2 (m, overlap, 5H), 1.32 (s, _CH3); 1.2 (s, 3H, CH ₃ );

¹³ C NMR (75 MHz, CDCl 3): δ 176.5 (CO), 67.7, 63.4, 53.0, 51.3, 44.0, 38.3, 36.7, 20.5 , 18.3.

Example 6

1,4-Dimethyl-2-endo- (3 'pyridyl) -3-exo-carboxymethyl-7-

Preparation of azabicyclo [2.2.1] heptane (14a) and the exopyridyl endocarboxyl isomer of this compound (14b)

Following the procedure described for the preparation of compound 13, the title isomers were obtained in the form of a 94: 6 inseparable mixture from the corresponding osmium complex mixture.

Test Data for Compound 14a: 1 H-NMR (300 MHz, CDCl ₃ )? 8.45 (m, 2H, H 2 'and H 6'overlap); 7.49 (dt, J = 7.8, 1.5 Hz, 1H, H4 '), 7.23 (dd, J = 7.8, 4.8 Hz, 1H, H5'), 3.64 ( s, 3H, _CH3 O), 3.29 (dd, J = 5.9, 2.1 Hz, 1H, H2), 2.95 (d, J = 5.9 Hz, 1H, H3), 2 62 (br s, 1H, NH), 1.85-1.6 (m, 2H, CH ₂ 's);

1.5 (m, 1H); 1.35 (m, 1H); 1.29 (s, 3H, CH ₃ ), 1.26 (s, 3H, CH ₃ );

¹³ C-NMR (75 MHz, CDCl ₃ ): d 175.7 (CO), 149.8 (CH),

148.2 (CH), 135.3 (CH), 134.1 (C), 123.1 (CH), 67.6 (2Xc overlap), 58.7 (CH), 58.3 (CH), 51.7 (CH ₃ O), 38.6 (CH ₂ ), 30.3 (CH ₂ ), 19.3 (CH ₃ ), 18.7 (CH ₃ ).

Test data for 14b: ¹ H NMR (300 MHz, CDCl ₃ ) δ 3.36 (d, J = 6 Hz, H 2), 2.8 (dd, J = 6, 2 Hz, H 3).

Example 7

1,4-Dimethyl-2-endo- (3'-pyridyl) -3-exo- (hydroxymethyl) -7-

Preparation of azabicyclo [2.2.1] heptane (15)

Compound 14 was reduced with lithium aluminum hydride in ether to give a clear resin product after workup of the aqueous reaction mixture.

¹ H-NMR (300 MHz, CDCl ₃ ) δ 3.87 (dd, J = 10.6, 2.8 Hz, 1H, 1/2 CH ₂ OH), 3.46 (dd, J = 10.6 , 3.0 Hz, 1H, 1/2 CH ₂ OH),

3.16 (dd, J = 5.0, 1.9 Hz, 1H, H2), 1.5 (s, 3H, _CH3), 1.25 (s, 3H, _CH3).

Example 8

1,4-Dimethyl-2-endo- (3'-pyridyl) -3-exo-phenylsulfonyl-7-

Preparation of azabicyclo [2.2.1] heptane (16a) and exopyridyl, endophenylsulfonyl isomer (16b)

The procedure for the preparation of compounds 13 and 14 is followed; An isomeric mixture of 7-azanorbornane compounds is thus obtained. ¹ H NMR peaks of the major isomers: 3.6 (d, J = 7 Hz, 1H, Ch endo)> 2.95 (dd, J = 7, 1.5 Hz, 1H, Ch _exo ), 1.85 (s, 3H, CH ₃ ),

1.25 (s, 3H, CH ₃ ).

Example 9 Preparation of [Os (NH ₃ ) s (2,3-n ² -2,5-dimethylpyrrole)] (Otf) ₂ (17)

1.445 g (2.0 mmol) of [Os (NH ₃ ) ₅ OTf] OTf _{2 are} dissolved in 1.5 g of N, N-dimethylacetamide, to which 1.5 g (16 mmol) of

2,5-Dimethylpyrrole and 1.0 g (41 mmol) of activated Mg 0 are added and the suspension is stirred for 45-60 minutes. The suspension was administered i

it was then filtered through a medium porosity filter into 150 mL CH ₂ Cl ₂ to give a pale yellow precipitate, which was collected by filtration, washed with CH ₂ Cl ₂ and ether and dried. 1.23-1.31 g (92-98%) of a pale yellow powder are obtained.

Example 10

5,6-βχο-η ² -θ8 (ΝΗ ₃ ) ί-1,4-dimethyl-1,2-exo-methoxycarbonyl-7-azabicyclo [2.2.1] hept-5-ene (Otf) ₂ (18)

The 2,5-dimethylpyrrole complex (669 mg, 1.0 mmol) was suspended in methyl acrylate (2 g) and stirred for 1 hour. Acetonitrile (1 mL) was added to dissolve the solid and the resulting solution was added to ether (50 mL) with stirring. The precipitate was collected by filtration, washed with ether and dried to give 730 mg (97%) of an off-white powder.

1 H-NMR (300 MHz, CD ₃ CN) δ 3.97 (bs, 3H, trs-NH ₃ ), 3.65 (s, 3H, CH ₃ O); 3.34 (broad s, 12H, cis -NH ₃ ),

3.17 (d, J = 6.3 Hz, 2H, H5 or H6), 3.13 (d, J = 6.3 Hz, 1H, H6 or H5), 2.77 (dd, J = 8, 1, 4.2 Hz, 1H, H 2), 2.14 (broad s, 1H, NH), 2.05 (dd, J = 11.6, 8.1 Hz, 1H, H 3 _end0 ), 1.63 (dd, J = 11.6, 4.2 Hz, _Η3 β χο), 1.39 (s, 3H, _CH3), 1.24 (s, 3H, _CH3), ¹³ C-NMR (75 MHz , CD ₃ CN) d 176.4 (CO), 75.7 (C), 71.0 (C), 59.1 (CH), 58.0 (CH), 55.3 (CH), 51, 6 (OCH ₃ ), 47.1 (CH ₂ ), 18.3 (CH ₃ ), 15.9 (CH ₃ );

Elemental analysis based on the formula Ci ₂ H ₃₀ N ₆ O 8 S ₂ F ₆ OS:

calculated:

C, 19.10; H, 4.01;

N, 11.14;

Found: C, 18.57; H, 3.96; N, 11.02.

Example 11

Preparation of Pentamine-Osmium-Pyrrole Complex: 2,3-η ² - [Os (NH ₃ ) _e ] -ligand] (Otf) ₂ , wherein the ligand is pyrrole or N-methylpyrrole

723 mg (1.0 mmol) of [Os (NH ₃ ) ₅ OTf] (OTf ₂ ), 1 g of N, N-dimethylacetamide, 3 g of DME, 1 g of pyrrole or N-methylpyrrole and 5 g of magnesium are added and the mixture is stirred for 1 hour. The solution was filtered through a 60 mL medium-mesh glass filter, using 10-15 mL of DME, and the filtrate was added dropwise to 150 mL of methylene chloride. The resulting precipitate was collected by filtration, washed with methylene chloride (20 mL) and ether (2 x 20 mL), and then dried under nitrogen. The reaction yields 90-95% of a yellow-orange product containing about 8% of binuclear impurities.

Example 12

Preparation of pentaamine-osmium-cycloadduct complexes

The pentaamine-osmium pyrrole complex prepared in Example 11 was treated with excess dipolarophil (3-30 equivalents) in acetonitrile or in a solution containing N, N-dimethylacetamide. After 1-10 hours, the solution is added with stirring to ether or methylene chloride (20 mL of ether / 1 g of acetonitrile or 25 mL of methylene chloride / 1 g of N, N-dimethylacetamide). The resulting precipitate was worked up as described in Example 11, yielding 85-95%.

yl

Example 13

Preparation of pentamine-osmium-cycloadduct complexes using the same flask, without isolation of the intermediate

In the same manner as in Example 11, a dipolarophilic material (such as methyl acrylate) is added directly to the reaction mixture to form the complex from red. After a suitable reaction time (e.g. 1-10 hours), the mixture is filtered to remove magnesium and the filtrate is added with stirring to a 1: 1 mixture of methylene chloride / ether (100 mL for each gram of Ν, Ν- dimethylacetamide). The solid was isolated as described in Example 11 to give the cycloadduct complex as a mono-N, N-dimethylacetamide solvate in about 95% yield.

Example 14

Preparation of 7-Azanorbornanes from the pentaamino-osmium-cycloadduct complex; using the same flask, without isolating the intermediate

The cycloadduct complex prepared in Example 13 (1.0 mmol) was dissolved in 4 g of acetonitrile, protonated with 3 to 5 equivalents of triflinic acid, and treated with 1 equivalent of DDQ. The resulting dark colored solution was transferred to a 50 mL round bottom flask using an additional 20 mL of acetonitrile for washing, 10% palladium on charcoal (about 0.5 g, 40 mol%) was added and the mixture was pressurized with 1 atmosphere of hydrogen (bottle). hydrogenated for a suitable period of time (2-20 hours). (In the pyrrole-containing complexes, a reductive amination occurs on the nitrogen atom in the absence of a ··· · substituent; the N-ethyl derivative is formed in the acetonitrile medium. In these cases, the solvent is evaporated and the reduction is carried out in methanol).

Workup: The reaction mixture was filtered through Celite to remove the Pd / C catalyst, the filter cake washed with acetonitrile (or methanol) and the filtrate concentrated. The residue was dissolved in water (about 10-15 mL), transferred to a separatory funnel, made basic with 10% aqueous Na ₂ CO ₃ (20 mL), and extracted with 3 x 40 mL portions of methylene chloride. The extract was dried over anhydrous magnesium sulfate and concentrated to give crude 7-azanorbornane.

Treatment B: After hydrogenation, the reaction mixture is treated with 1 mL of NH ₄ OH, diluted with an equal volume of methylene chloride (about 30 mL), filtered through 20 mL of silica gel, and filtered with a 30 mL glass funnel. The flask and silica gel were washed with 2 x 30 mL of a 1: 1 mixture of methylene chloride / acetonitrile (or methanol) (containing about 3-5% NH ₄ OH), and the eluent was combined and evaporated to give crude 7-azanorbornane. we get derivatives.

Example 15

Preparation of 2-methoxycarbonyl-7-methyl-7-azabicyclo [2.2.1] heptanes

The title compounds were obtained as a 1: 1 mixture of isomers in 66% overall yield; as starting material ··· · il

- 43 ♦ · · · * ·· «« · ··

N-methylpyrrole and methyl acrylate were used as described in Examples 13 and 14 (Processing Method B). The isomers were separated by preparative thin layer chromatography using HMDS / methanol / methylene chloride (1: 1: 5). Exo isomer (1): R _f = 0.76; ¹ H-NMR (CDCl ₃ ) δ 3.66 (s, 3H, CH ₃ O); 3.62 (d, J = 4.2 Hz, 1H, H4), 3.30 (t, J = 4.0 Hz, 1H, H4), 2.40 (dd, J = 9.6,

5.4 Hz, 1H, H 2), 2.21 (s, 3H, CH ₃ N), 2.18 (m, 1H); 1.86 (m, 2H); 1.57 (dd, J = 12.6, 9.6 Hz, 1H, H3 _end o), 1.33 (m, 2H); ¹³ C NMR _(CDCl3): δ 174.6 (C, CO), 64.2 (CH, C1 or C4), 61.1 (CH, C4 or C1), 51.9 (CH _3, CH ₃ O) , 47.4 (CH, C ₂ ), 34.5 (CH ₃ , CH ₃ N), 33.3 (CH ₂ ), 26.7 (CH ₂ ), 26.2 (CH ₂ );

Endo isomer (2): R _f = 0.62;

¹ H-NMR (CDCl 3) δ 3.65 (s, 3H, CH 3 O); 3.44 (t, J = 4.5 Hz, 1H, H1 or H4), 3.21 (t, J = 4.5 Hz, 1H, H4 or H1), 3.08 (m, 1H, H2) ; 2.26 (s, 3H, CH 3 N); 1.95 (m, 1H); 1.75 (m, overlap, 3H); 1.36 (m, 2H); ¹³ C-NMR (CDCl 3, 50 ° C) δ 174.3 (C, CO), 64.1 (CH, C 1 or C 4), 62.1 (CH, C 4 or C 1), 51.4 (CH ₃ , CH ₃ O), 45.2 (CH, C 2), 34.4 (CH ₃ , CH ₃ N), 30.6 (CH ₂ ), 28.0 (CH ₂ ), 24.2 (CH ₂ ).

The picrate salt of the mixture of the two isomers was recrystallized from ethanol, m.p. 102-108 ° C;

Analysis for C ₁₅ Hi8N 0g ₄ Calc'd:

Calculated: C, 45.23; H, 4.55; N, 14.07;

Found:

C, 45.42; H, 4.59;

N, 14.10.

Example 16

Preparation of 2-Cyano-7-methyl-7-azabicyclo [2.2.1] heptanes

The title compounds were obtained as a 1: 1 mixture of isomers in a total yield of 57%; starting materials N-methylpyrrole and acrylonitrile were prepared as described in Examples 13 and 14 (work up according to Method B). The isomers were separated by preparative thin layer chromatography using HMDS / methanol / methylene chloride (1: 1: 8).

Exo isomer (3): _Rf = 0.71.

¹ H-NMR (CDCl 3) δ 3.53 (d, J = 3.3 Hz, 1H, H 1), 3.37 (t, J = 3.8 Hz, 1H, H 4), 2.44 (dd, J = 9.3, 5.1 Hz, 1H, H 2), 2.36 (s 3H, CH ₃ N), 2.1 (m, 1H), 1.83 (m, 2H); 1.75 (dd, J = 12.6, 9.3 Hz, 1H, H3endo). 1.3 (m, 2H);

¹³ C-NMR (CDCl 3) δ 122.7 (C, CN), 65.5 (CH, C 1 or C 4), 60.8 (CH, C 4 or C 1), 35.7 (CH ₂ ), 35.3 (CH ₃ ), 31.9 (CH), 27.5 (CH ₂ ), 26.9 (CH ₂ );

Endo isomer (4): R _f = 0.55;

¹ H-NMR (CDCl ₃ ) δ 3.44 (t, J = 4.5 Hz, 1H, H1 or H4), 3.29 (t, J = 4.5 Hz, 1H, H4 or H1), 2 92 (dtd [11 line pattern], J = 12, -4.8, 1.8 Hz, 1H, H2), 2.26 (s, m overlap, 4H, CH ₃ N and _Η3 β χο) 2 0-1.8 (m, 3H); 1.57 (dd, J = 12.3, 5.1 Hz, 1H, H3endo), 1.45 (m, 1H);

• ·· · • ··· • - · · <1 .......

- 45 ¹³ C-NMR (CDCl ₃ , 50 ° C) δ 121.7 (C, CN), 63.8 (CH, C 1 or C 4), 61.6 (CH, C 4 or C 1), 34.6 ( CH ₂ ), 34.3 (CH ₃ , CH ₃ N), 29.2 (CH, C 2), 27.9 (CH ₂ ), 24.1 (CH ₂ ).

The picrate salt of the mixture of the two isomers is recrystallized from ethanol; mp 218-224 ° C.

Elemental analysis based on C14H15N5O7:

Calculated: C, 46.03; H, 4.14; N, 19.17;

Found: C, 45.85; H, 4.08; N, 18.88.

Example 17

Preparation of trans-2,3-bis-methoxycarbonyl-l-7-azabicyclo [2.2.1] heptane

The title compound was obtained in a total yield of 42%; pyrrole and dimethyl fumarate are used as starting materials; the procedure was carried out as described in Examples 11 and 12 (using acetonitrile as solvent). Hydrogenation was carried out as in Example 14 (using methanol as solvent; reaction time about 2 hours; work-up using Method A).

¹ H-NMR (CDCl ₃ ) δ 3.95 (t, J = 4.5 Hz, 1H, H 4), 3.84 (d, J = 4.8 Hz, 1H, H 1), 3.70 (s , 3H, _CH3 O), 3.695 (s, 3H, _CH3 O);

3.22 (td, J = 4.8, 1.8 Hz, 1H, H3), 3.03 (d, J = 4.8 Hz, 1H, H2), 2.55 (broad s, 1H, NH ), 1.8-1.3 (overlap m, 4H);

¹³ C-NMR (CDCl ₃ ) δ 174.8 (C, CO), 172.1 (C, CO), 61.8 (CH, C 1 or C 4), 59.1 (CH, C 4 or C 1), 52 , 3 (CH), 52.1 (CH ₃ , CH ₃ O), 52.0 (CH ₃ , CH ₃ O), 50.1 (CH), 28.7 (CH ₂ ), 24.9 (CH ₂ ).

• ·· e í!

- 46 1 Example 8

Preparation of Hexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3 (2H) -dione

The title compound was obtained as a 4: 1 mixture of exo and endo isomers in a total yield of 39%; starting with pyrrole and N-phenyl maleic acid imide, prepared as in Examples 11 and 12 (using acetonitrile as solvent), hydrogenating as in Example 14 (using methanol as solvent), reaction time: 2 hours; the processing is carried out in accordance with Method A. The crude product obtained was purified by preparative thin layer chromatography (20 x 20 cm, 2 mm) eluting with a gradient of ether containing about 4% concentrated ammonium hydroxide and 5, 10 and 20% methanol, respectively. Ether and methanol mixture extracted two bands F1 _(Rf = 0.75, 3% ammonium hydroxide and 10% methanol in ether). The resulting material was recrystallized from ethyl acetate / petroleum ether to give a colorless crystalline product; mp 206-209 ° C; exo isomer.

1 H-NMR (CDCl ₃ ) δ 7.5-7.3 (m, 5H, Ph); 4.15 (t, J = 2Hz, 2H, H1, H4), 2.86 (s, 2H, H2, H3); 1.7 (m, 4H, 2 X _CH2), 1.54 (br s, 1H, NH);

¹³ C-NMR (CDCl ₃ ) δ 177.3 (CO), 132.1 (C), 129.0 (CH),

128.5 (CH), 126.5 (CH), 59.9 (CH, C1, C4), 49.0 (CH, C2, C3), 29.5 _(CH2).

From the second fraction (Rf = 0.21), the endo-isomer is recovered: 1 H-NMR δ 7.6-7.2 (m, 5H, Ph); 4.18 (wide s, 2 Η, H1 and · 9 · il * «·

- 47 Η4), 3.64 (br s, 1 Η, NH), 3.41 (br s, 2 H, _H2 and H3), 1.8-1.6 (m, 4H).

¹³ C-NMR δ 175.9 (C), 132.0 (C), 129.7 (CH), 129.3 (CH), 126.9 (CH), 59.6 (CH), 51.5 (CH), 26.5 (CH ₂ ).

Example 19

Preparation of 8-Ethylhexahydro-2-phenyl-exo-4,7-imino-1H-isoindole-1,3 (2H) -dione

This compound was prepared by hydrogenating the hexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3 (2H) -dione in the presence of acetonitrile (see Example 14; reaction time: 18). hours; processed by method A). The crude product obtained is chromatographed on silica gel (3.5 x 13 cm column). Elution with ether gave 56 mg (21%) of the title compound (R _f = 0.8; NH ₄ OH containing ether). Further elution was carried out with 10% methanol and 3% concentrated NH ₄ OH to give a second fraction, 69 mg of crude hexahydro-2-phenyl-4,7-imino-1H-isoindole-1,3 (2H) -. containing d ion (R _f = 0.2; ether containing NH ₄ OH). The first fraction was purified on charcoal, filtered, and the filtrate was concentrated, and the residue was recrystallized from ethyl acetate / petroleum ether. Yield = 21 mg; the product is obtained in the form of sparkling colorless crystals; 126-128 ° C.

¹ H-NMR (CDCl ₃ ) δ 7.5-7.25 (m, 5H, Ph); 3.82 (t, J = 2.2 Hz, 2H, H 1, H 4), 2.80 (s, 2H, H 2, H 3); 2.37 (q, J = 7.2 Hz, 2H, NCH ₂ ), 1.93 (m, 2H, H 5 _exo , Η 6θχ ₀ ); 1.51 (m, 2H, H5 _end0,

H6 _end0 ); 1.04 (t, J = 7.2 Hz, 3H, CH ₃ );

¹³ C-NMR (CDCl 3) δ 177.8 (CO), 132.4 (C, CT), 129.1 (CH), 128.5 (CH), 126.7 (CH), 62.6 (CH , C1, C4), 49.5 (CH,

C 2, C 3), 40.4 (CH ₂ N), 25.0 (CH ₂ ), 14.5 (CH ₃ ).

Example 20

Preparation of Hexahydro-1-hydroxy-2-phenyl-4,7-imino-1H-isoindol-3 (2H) -one

The exo-imide (25 mg, -0.1 mmol) prepared in Example 18 was treated with an excess of sodium borohydride (40 mg, -1.0 mmol) in 5 mL of ethanol and refluxed for 20 minutes. The ethanol is then distilled off, the residue is acidified with n hydrochloric acid and treated with Na ₂ CO ₃ and methylene chloride. The extract was evaporated to give 20 mg of crude product. Through preparative thin layer chromatography (eluting with 5% NH4 OH and ether 10 to 20% methanol gradient) to afford the title compound _(Rf = 0.25, 3% NH4OH and 10% methanol in ether); the resulting product is contaminated with small amounts of by-products.

¹ H-NMR (CDCl ₃ ) δ 6.44-7.2 (m, 5H, Ph); 5.22 (s, 1H, NCH (OH)); 3.82 (d, J = 2Hz, 1H), 2.60 (d, J = 2Hz, 1H), 2.71 (d, J = 10Hz, 1H), 2.08 (d, J = 10 Hz, 1H), 1.63 to 1.3 (m, overlap, 6H, 2 X _CH2, NH, OH).

Example 21

Preparation of Exo-2-Aminomethyl-7-methyl-7-azabicyclo [2.2.1] heptane mg (0.4 mmol) of the nitrile derivative prepared in Example 16 with excess lithium aluminum hydride (30 mg, 0.79) mmol) in 10 mL of ether solution with stirring. After 5 minutes, a white slurry formed, quenched with methanol (0.1 g) followed by water (0.1 g), acidified with 1M HCl, and basified with concentrated NH ₄ OH; then extracted with methylene chloride. The extract was dried and concentrated to give the corresponding primary amine derivative as an oil (17 mg, 30%).

¹ H-NMR (CDCl ₃ ) δ (ppm): 3.18 (t, J = 3.9 Hz, 1H, H 4), 3.03 (d, J = 3.9 Hz, 1H, H 1), 2.70 (dd, J = 12, 7.8 Hz, 1H, 1/2 CH ₂ N), 2.51 (dd, J = 12, 6 Hz, 1H, 1/2 CH ₂ N),

2.22 (s, 3H, CH ₃ N), 1.86 (m, 2H); 1.6-1.2 (m, 7H, CH ₂ + NH ₂ overlap).

Example 22

Preparation of Exo-2- (1-pyridylmethyl) -7-methyl-1-7-azabicyclo [2.2.1] heptane mg (0.121 mmol) of the primary amine from Example 21 25 mg (0.189 mmol). 5-dimethoxytetrahydrofuran was treated with 0.1 g acetic acid and kept in an oil bath at 150 ° C for 5 minutes. The reaction mixture was basified with 10% aqueous Na ₂ CO ₃ and extracted with methylene chloride to give a product mixture of 8 · · · · · · · · · · · · · · · (about 30%) crude exo-2- ( 1-pyrrolylmethyl) product is obtained by preparative thin layer chromatography; for this step, a 1: 1: 8 mixture of hexamethyldisilylase / methanol / methylene chloride was used.

¹ H-NMR (CDCl 3) δ 6.68 (s, 2H); 6.18 (s, 2H); 3.92 (dd, J = 15, 12 Hz, 1H, 1/2 CH ₂ N), 3.72 (dd, J = 15, 7 Hz, 1H, 1/2 CH ₂ N),

3.22 (m, 1H); 2.96 (m, 1H); 2.26 (s, 3H, CH ₃ N); 1.98 (m, 1H);

1.83 (m, 2H); 1.5-1.22 (m, 4H).

Example 23

Preparation of Exo-2-Hydroxymethyl-7-methyl-7-azabicyclo [2.2.1] heptane with a mixture of lithium aluminum hydride (10 mg, 0.264 mmol) in ether (5 mg) (0.243 mmol) and lithium aluminum hydride (10 mg, 0.264 mmol). treated. After 5 minutes, the reaction mixture was poured into methanol, acidified with 1N hydrochloric acid, basified with concentrated NH ₄ OH and extracted with methylene chloride. The extract was concentrated to give the desired product (11 mg, 32%).

¹ H NMR (CDCl ₃ ) δ 3.80 (dd, J = 9, 1 Hz, 1H, 1/2 CH ₂ O), 3.39 (dd, J = 9, 2 Hz, 1H, 1/2 CH ₂ O), 3.21 (t, J = 5 Hz, 1H, H 4),

3.19 (d, J = 4Hz, 1H, H 1), 2.18 (s, 3H, CH ₃ N), 1.82 (m, 3H);

1.7 (m, 1H); 1.5-1.2 (m, 4H).

yl

Example 24

Preparation of Exo-2-Benzoyloxymethyl-7-methyl-7-azabicyclo [2.2.1] heptane: mg (0.078 mmol) of the alcohol derivative of Example 23 with 34 mg (0.15 mmol) of benzoic anhydride. and treated with a mixture of 10 mg DMAP in methylene chloride. The product was purified by preparative thin layer chromatography (20 x 20 cm x 0.25 mm); using NH ₄ OH / methanol / ether 1: 3: 80; R _f = 0.6; Yield: 10 mg (52%).

1 H-NMR (CDCl 3) δ 8.05 (d, J = 7.2 Hz, 2H, ortho-H), 7.55 (t, J = 7.2 Hz, 1H, para-H), 7, 44 (t. J = 7.2 Hz, 2H, Meta-H),

4.18 (m, 2H, CH ₂ O, 3.22 (t, J = 3.9 Hz, 1H, H4), 3.18 (d, J =

3.6 Hz, 1H, H 1), 2.25 (s, 3H, CH ₃ N); 2.05-1.85 (m, overlap, 3H), 1.48 (dd, J = 12, 9 Hz, 1H, H3e _nd o), 1.34 (m, 3H).

Example 25

Preparation of the norbornane analogue of epibatidine by the Heck reductive method: exo-2- (3-pyridyl) bicyclo [2.2.1] heptane

This method of preparation is based on Larock, R. et al., J. Med. Soc. Chem. Comm. 1368 (1989)]. Norbornene (101 mg, 1.07 mmol), 3-iodopyridine (205 mg, 1.0 mmol), tetra-n-butylammonium chloride (287 mg, 1.03 mmol), 255 mg (3.03 mmol) Formic potassium salt and 28 mg (0.125 mmol) of palladium acetate and 1.2 g of dimethylformamide were added and the mixture was stirred at room temperature for 72 hours. The mixture was diluted with 10 ml of 10% aqueous Na ₂ CO ₃ solution and 1 ml of ether, and the separated aqueous phase was extracted again with ether. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated, and the residue was purified by preparative thin layer chromatography (20 x 20 cm, 2.0 mm, petroleum ether / ethyl acetate 1: 1, R _f = 0.5); This gave 73 mg (42%) of the title compound as an oily product.

¹ H-NMR (CDCl ₃ ) δ 8.42 (s, 1H, H 2 '); 8.33 (d, J = 4.5 Hz, 1H, H6 '), 7.43 (d, J = 7.8 Hz, 1H, H4'), 7.11 (dd, J = 7.8, 4.5 Hz, 1H, H5 '), 2.67 (dd, J = 8.7, 5.7 Hz, 1H, H2), 2.30 (m, 2H, 1H, H1 and H4); 1.8-1.2 (m, overlap, 8H, 4 X _CH2).

¹³ C-NMR (CDCl 3) δ 149.1 (CH), 146.3 (CH), 142.3 (C), 134.0 (CH), 122.9 (CH), 44.7 (CH), 42.5 (CH), 38.7 (CH ₂ ),

36.7 (CH), 35.9 (CH ₂ ), 30.3 (CH ₂ ), 28.6 (CH ₂ ).

B. Preparation of 7-Azabicyclo [2.2.1] heptane or heptene ring by Diels-Alder rearrangement

Alternatively, the active compounds or precursors of the present invention may be prepared by Diels-Alder rearrangement (Figs. 2a, 2b), wherein N- (electron withdrawing substituent) pyrrole is arylsulfonyl- (optionally substituted aryl or heterocyclic). -acetylene. The electron-withdrawing group at the N ⁷ position reduces the aromatic nature of the pyrrole ring and activates the ring to carry out the ring addition reaction.

The N- (electron-withdrawing substituent) pyrrole is arylsulfonyl- (optionally substituted aryl or heterocyclic) · ··· • V ····· · ··· ·

reaction with -acetylene gives 7- (electron withdrawing substituent) -2- (optionally substituted aryl or heteroaromatic group) -3-arylsulfonyl-7-azabicyclo [2.2.1] hepta-2,5-diene (23 and 32). compounds). Conventional methods can be used to convert the resulting diene derivative to other 7-azabicyclo [2.2.1] heptane and heptene derivatives. For example, in the R ³ position, an alkyl or aralkyl group may be formed by reacting the saturated bicycloheptane 23 or 32 with n-butyllithium and R ³ and treating the resulting intermediate with a reducing agent. removing the arylsulfonyl group. (Julia, M. and Paris, J.M., Tetrahedron Letters, 49, 4833 (1973)). ^R5 and ^R6 can be applied to groups of 24-labeled compound such that the double bond is reacted in conventional manner [see Advanced Organic Chemistry, Carey and Sundberg, WOOD RJ, 167-218. Plenum Publishing Co. (1990). Examples of further reactions which may be carried out include, but are not limited to, hydrogenation, treatment with boron hydrogen, hydrogen halogenation, hydroxylation, halogen hydrogenation, alkylation, carbonyl or dihalocarbonyl addition, epoxidation, ring-opening reaction, and nucleophilic reactions. such as alkoxides, amines, alkylsulfide, halide or hydroxide.

The reactive chlorine atom in compounds 24 and 25 can be readily substituted by a nucleophilic tubular port such as an alkoxy group such as methoxy, or an alkylthio, hydroxy, amino, cyano, azide, bromide, iodide or dimethylamino group. group, respectively.

The reaction of the N- (electron withdrawing substituent) pyrrole with the arylsulfonyl (optionally substituted aryl or heterocyclic group) acetylene is carried out in the presence of an excess of N- (electron withdrawing substituent) pyrrole or a solvent such as toluene, dimethyl, formamide, diethoxyethane or other inert solvents. The molar ratio of pyrrole to dienophilic compound may be arbitrary, as long as this ratio provides a satisfactory yield of product, generally in the range of from 0.5: 1 to 50: 1, preferably from (1-5): 1.

The reaction may be carried out at any temperature, provided the desired product is obtained, usually at room temperature to 150 ° C, and the reaction mixture is allowed to complete until the reaction is complete, typically from 1 hour to 72 hours. in a reactor at a pressure of 1 atmosphere or more.

There are several ways of removing the N-electron withdrawing group, in particular the N-carbonylmethoxy protecting group, from the desired 7-azabicyclo [2.2.1] heptane or heptene compound. Hydrolysis of compound (25) with potassium hydroxide in methanol to replace the moderately reactive chlorine on the pyridine ring with methoxy. Treatment of 25 with methyl lithium yields N-acetyl-epibatidine (the same product as the product obtained by acetylation of rac-epibatidine as described below), stops the formation of this compound and further treatment with methyl lithium no breakage of the compound occurs. This phenomenon is consistent with the known stability of N-acetyl-epibatidine. Treatment of 25 with hydrogen bromide at room temperature for 24 hours in acetic acid may remove the protecting group. The product was chromatographed on silica gel using a mixture of ethyl acetate, methyl chloride and ammonia-methanol as the eluent: rac-epibatidine (19, 25%), rac-endo-epibatidine (19 ', 28.4%) and unchanged yielding carbamate (25, 20%). It should be noted that the starting material remaining in the reaction mixture is a pure endo-isomer of 25, which indicates that there is some stereoselectivity when the N-carbonylmethoxy group is cleaved with hydrogen bromide. The exo-isomer appears to be cleaved at a higher rate than the endo-isomer, presumably due to the proximity of the pyridyl and carbamate groups. The rac-epibatidine thus obtained had a melting point of 50-51 ° C, and the resulting compound was very pure as confirmed by spectral data.

i) N- (electron withdrawing substituent) -pyrrole

Many substituted pyrrole derivatives are known which can be easily converted to N- (electron withdrawing substituent) pyrrole, which can then be converted to the 7-azabicyclo [2.2.1] heptane or heptene via Diels-Alder rearrangement. Examples of these compounds include:

3- (thioalkyl) -pyrrole such as 3- (SCH ₃ ) -pyrrole; 2,5-dialkylpyrrole as

2,5-d breast-feeding 1-pyrrole; 3,4-dihaloalkylpyrrole such as 3,4-bis (trifluoromethyl) pyrrole, 2-alkylpyrrole such as 2-methylpyrrole; 2-alkoxyalkylpyrrole such as 2-methoxymethylpyrrole; 2-alkylthioalkylpyrrole such as 2-methylthiomethyl-pyrrolo; 2-Dimethyl-1-aminoamino-1-pyrrole such as 2-dimethylaminomethylpyrrole; alkylpyrrole-2-acetate such as dimethylaminomethylpyrrole: alkylpyrrole-2-acetate such as methylpyrrole-2-acetate; 2-a-coxi-a-coxi - a k-1-pyrrolo such as 2-methoxymethoxyethylpyrrole; 3-aryloxyalkylpyrrole such as 3-benzyloxymethylpyrrole; 2-alkoxypyrrole such as 2-methoxypyrrole; 3-alkoxypyrrole such as 3-methoxypyrrole; 3-aryloxypyrrole such as 3-benzyloxypyrrole; 3,4-dialkylpyrrole and 3-alkylpyrrole such as 3-methylpyrrole and

3,4-dimethylpyrrole; 1,6- and 4,5-alkylidene-pyrrole such as 4,5,6,7-tetrahydroindole and 2-methyl-4,5,6,7-tetrahydroindole.

The N-substituent on the pyrrole ring may be any electron withdrawing group that activates the ring to effect addition of dienophile derivatives to the ring. Preferably the nitrogen atom has a carbonyl methoxy substituent, but other electron withdrawing groups such as carbonylbenzyloxy, tert-butoxycarbonyl or optically active alkoxycarbonyl such as (+) or (-) - menthyl an oxycarbonyl group may be present.

i ii) Arylsulfonyl- (optionally substituted aryl or heteroaromatic group acetylene)

In this step, a compound of the formula aryl-SO ₂ CsC (optionally substituted aryl or heteroaromatic) is reacted with N- (electron withdrawing substituent) pyrrole or a derivative thereof.

Arylsulfonyl (optionally substituted aryl or heteroaromatic) acetylene may be prepared by methods well known to those skilled in the art. In one embodiment, as exemplified in Example 26, the compound is prepared by reacting a methyl (aryl) sulfonium lithium salt with an appropriately substituted aryl or heteroaromatic acid chloride to form 1- (aryl or heteroaromatic) -2-arylsulfonylethanone is obtained and is converted to the corresponding acetylene derivative via an enol phosphate intermediate (as described in Example 27). Any optionally substituted aryl or heteroaromatic acid chloride may be employed, including, but not limited to, the acid chlorides formed from the following acids: nicotinic acid, isonicotinic acid, 5-chloronicotinic acid,

6-methyl-nicotinic acid, 6-methoxy-nicotinic acid, 6-phenyl-nicotinic acid, 6-methoxy-nicotinic acid, 6-phenyl-nicotinic acid, 6-methyl-thio-nicotinic acid, 2-chloropyridine-4-carboxylic acid, 2, 6-dimethylpyridine-4-carboxylic acid, 1-methyl-2 (1H) -pyridone-3-carboxylic acid, 6-methylthio-nicotinic acid, 3-quinolinic acid, 4-quinolinic acid, 7-chloro-3-quinolinic acid, 6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid, 5-chlorothiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid, 5-methoxyindole-3-carboxylic acid, · · · · yl

1,2,5-thiadiazol-2-carboxylic acid. thiazole-5-carboxylic acid, 2-chlorothiazole-5-carboxylic acid, and 5-chloropyridazine-2-carboxylic acid. Examples of substituents on aromatic or heteroaromatic groups include, but are not limited to, alkyl, aryl, alkoxy, halogen, dialkylamino, alkylthio, hydroxy, hydroxyalkyl, and C (O) (alkyl). or aryl).

The aryl group attached to the sulfone group may be any aryl group which appropriately activates the acetylene group to act as a dienophile against the activated pyrrole and where the aryl group present does not interfere with the cycloaddition reaction. Examples of aryl include, but are not limited to, phenyl, p-alkylphenyl such as p-methylphenyl; halophenyl such as p-chlorophenyl, p-fluorophenyl and p-nitrophenyl. Fluoroalkane sulfonyl such as CF ₃ SO ₂ or C ₄ F ₈ SO _{2 can be} used to activate the aryl or heteroaryl acetylene.

The preparation of various arylsulfonyl (aryl or heteroaromatic) acetylene derivatives is described by Bhattacharya, S.N. et al., Organomet. Chem. Synth. 1, 145 (1970)], the reaction of aryl or heteroaromatic trimethylsilyl acetyl with tosyl chloride in the presence of a Lewis acid catalyst such as aluminum trichloride is described by Sakamoto T. et al., 1983, Synthesis 312.

The preparation of the active ingredient by the Diels-Alder reaction, wherein N- (electron withdrawing substituent) pyrrole is reacted with an yl arylsulfonyl (optionally substituted aryl or heterocyclic group) acetylene, is described in detail in the following examples. The examples illustrate the preparation of the compounds without limitation. As mentioned above, this process can be combined with conventional other synthetic methods to produce a variety of products falling within the scope of the invention. The numbering of the compounds is shown in Figure 2.

Example 26

Preparation of 1- (2-Chloro-5-pyridyl) -2-phenylsulfonylethanone (9) Methylphenylsulfone (g) was dissolved in 400 ml of anhydrous tetrahydrofuran and cooled to -30 ° C with 128 ml of (4 equivalents) of 2.5 mol / l n-butyllithium. The resulting solution was stirred at -30 ° C for 30 minutes. Subsequently, a solution of 26 g of 6-chloronicotinic acid chloride in 100 ml of tetrahydrofuran is added dropwise over about 30 minutes. The mixture was stirred at the above temperature for 30 minutes and then poured into about 100 ml of a saturated ammonium chloride solution. The organic layer was separated and the aqueous layer was extracted three times with chloroform. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. Removal of the solvent gave a brown solid which was triturated with 150 mL of methanol to give 7.06 g of a pale yellow solid. An additional portion of product (11.75 g) ··· · il

60 can be recovered from the mother liquor by purification of the mother liquor by a short chromatography column using silica gel and 50% ethyl acetate in petroleum ether as eluent. Overall yield: 18.81 g (49.7%). Mp 152-153 ° C.

MS (CI) m / z 296, 298 (M + 1).

Proceeding as described above and using the acid chloride of the following acids for the condensation reaction, the corresponding ketosulfone derivatives are obtained; nicotinic acid, isonicotinic acid, 5-chloro-nicotinic acid, 6-methyl-nicotinic acid, 6-methoxy-nicotinic acid, 6-phenyl-nicotinic acid, 6-methyl-thio-nicotinic acid, 2-chloro-pyridine-4-carboxylic acid,

2,6-Dimethyl-pyridine-4-carboxylic acid, 1-methyl-1-2 (1H) -pyridone-3-

carboxylic acid, 6-methylthio-nicotinic acid, 3-quinolinic acid, 4-quinolinic acid,

7-chloro-3-quinolinic acid, 6-methoxy-3-quinolinic acid, isoquinoline-4-carboxylic acid, 5-chlorothiophene-2-carboxylic acid, pyrimidine-5-carboxylic acid, 5-methoxyindole-3-carboxylic acid, 2,4-thiadiazole-2-carboxylic acid, thiazole-5-carboxylic acid, 2-chloro-thiazole-5-carboxylic acid, 5-chloro-pyridazine-2-carboxylic acid.

Example 27

Preparation of 2-chloro-5-pyridylphenylsulfonylacetylene (22)

To a suspension of 840 mg of 60% sodium hydride (washed with ethyl ether) in 100 ml of tetrahydrofuran was added a solution of 3.34 g (11.3 mmol) of 20 in 100 ml of anhydrous tetrahydrofuran. After stirring for 10 minutes, diethyl chlorophosphate (1.88 mL, 11.3 mmol) was added in one portion. After stirring overnight at room temperature, the mixture was cooled to -78 ° C and treated in portions with 1.35 g of potassium per liter.

- 61-Butoxide is added. The brown solution was stirred at -78 ° C for an additional 10 minutes and then allowed to warm to about 30 ° C. After addition of water, the aqueous phase is extracted with methylene chloride, the organic phase is dried and concentrated in vacuo, the residue is purified on a silica gel column (eluted with 25% ethyl acetate in petroleum ether). Evaporation of the solvent gave 1.2 g of a white product; mp 140-141 ° C.

MS (CI) m / z 278, 280 (M + 1), 38%.

Proceeding as described above, however, using another heterocyclic ketosulfone derivative listed in Example 26 instead of the compound of Formula 20, affords the corresponding acetylene derivative.

Example 28

Preparation of N-methoxycarbonylpyrrole (21) Potassium (5.85 g, 0.15 mol) was added in portions to a solution of pyrrole (0.145 mol) in hot cyclohexanone (80 ml). The mixture was refluxed for 1 hour. To the cooled mixture was slowly added methyl chloroformate (15 g, 0.16 mol). After the addition was complete, the mixture was stirred at room temperature for 30 minutes. During this time, 2.5 ml of trimethylsulfoxide was added as a catalyst. The reaction mixture is then poured into ice water, the organic phase is separated off, and the aqueous phase is extracted with ether. The combined organic layers were washed with 10% sodium bicarbonate solution and then with saturated sodium chloride.

• * · ιί

Wash with 62 solution and then dry over anhydrous magnesium sulfate. Removal of the solvent gave 17.4 g of a liquid product. The resulting material was distilled to give 16.5 g of N-methoxycarbonylpyrrole (21) as a colorless liquid; yield: 91%. The product should be stored at -20 ° C.

Proceeding as above, we can obtain 2,5-dimethylpyrrole,

3,4-bis (trifluoromethyl) -pyrrol, 2-methyl-1-pyrrolo, 2-methoxymethyl-pyrrol, 2-methyl-thiomethyl-pyrrol, 2-dimethylaminomethyl pyrrole, methylpyrrole-2-acetate, 2-methoxymethoxymethylpyrrole, 3-benzyloxymethylpyrrole, 2-methoxypyrrole, 3-methoxypyrrole and 3-benzyloxypyrrole N-methoxycarbonyl-. N-benzyloxycarbonyl and N-tert-butoxycarbonyl.

Example 29

Preparation of 7-methoxycarbonyl-2- (2-chloro-5-pyridyl) -3-phenylsulfonyl-7-azabicyclo [2.2.1] 2,5-diene (23)

2-Chloro-5-pyridylphenylsulfonylacetylene (22) (1.12 g, 40.3 mmol) was dissolved in N-carbonyl methoxypyrrole (21) (8.0 g). The mixture was stirred in a sealed flask at 80-85 ° C for 24 hours. The mixture was concentrated in vacuo to give N-carbonylmethoxypyrrole, which was purified by chromatography on a silica gel column using 25-50% ethyl acetate in petroleum ether as eluent; 0.2 g of acetylene 22 and 1.21 g of a pale brown product are obtained. The crude product obtained was triturated with methanol to give 0.94 g of a white solid (58% or 70% of the recovered starting material).

- based on 63 substances). Melting point: 101 ° C. MS (CI) m / z 403;

405 (M + 1). When the arylsulfonylacetylene derivative described in Example 27 is used instead of Compound 22, the corresponding Diels-Alder adduct is obtained.

Example 30

Preparation of 7-methoxycarbonyl-5- (2-chloro-5-azabicyclo [2.2.1] hept-2-ene (24)

Compound 23 (0.726 g, 1.9 mmol) was dissolved in a mixture of dry methanol (1.0 g, 8.0 mmol) in dry methanol (50 mL) and tetrahydrofuran (7 mL). To this mixture was added 3.0 g of 6% sodium amalgam in two portions at -20 ° C under nitrogen. While stirring, the mixture was allowed to warm to room temperature over about 2 hours and then stirred at room temperature for an additional 1 hour. The upper phase is decanted off and the residue is washed with methanol. Water and 10% hydrochloric acid were added to the combined methanol extracts to adjust the pH to 6 and then most of the methanol was evaporated in vacuo. The mixture was then extracted with methylene chloride. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column using 33% ethyl acetate in petroleum ether as eluent; This gave 215.3 g (42.9%) of a colorless oily product. The ¹ H NMR data show that the product is the exo and endo isomers of a 1: 2 mixture of.

• ·· * · · '· · * ····

- 64 MS (CI) m / z 265, 267 (M + 1).

¹ H NMR 6.01-6.53 (2H, H _{5 6} ), 4.61-4.91 (2H, H, ₄ ).

When the other Diels-Alder adduct described in Example 29 is treated with sodium amalgam as above, the correspondingly substituted 7-azabicyclo [2.2.1] hept-2-ene is obtained.

Example 31

Preparation of 7-methoxycarbonyl-1-2- (2-chloro-5-pyridyl) -7-azabicyclo [2.2.1] heptane (25)

Compound 24 (a mixture of isomers) (178.4 mg, 0.674 mmol) was dissolved in 10 mL of methanol containing 10% palladium on carbon. The mixture was hydrogenated at 1 atmosphere. After 18 ml of hydrogen (5 minutes), the catalyst was removed by filtration and the methanol was distilled off in vacuo; This gave 165 mg (92%) of a colorless oily product. The ¹ H NMR data indicate that the resulting product of the exo and endo isomers in a 1: 2 as eluent.

MS (CI) m / z 267, 269 (M + 1). 1 H NMR 4.21-4.44 (2H, H ₁₄ ).

Proceeding as above, the other substituted 7-azabicyclo [2.2.1] hept-2-ene derivatives described in Example 30 are hydrogenated to give the corresponding substituted 7-azabicyclo [2.2.1] heptane derivatives.

Example 32

Preparation of racemic epibatidine (19) and endo-epibatidine (19 *) 25 mg (0.338 mmol) of compound 25 are dissolved in 2.5 ml of hydrobromic acid (33% in acetic acid). The mixture was stirred at room temperature for 20 hours and then concentrated in vacuo; the residue was dissolved in water and the solution was extracted with ethyl ether to give 26 mg of starting material. The aqueous phase was basified to pH 11 with potassium hydroxide and then extracted with methylene chloride. The combined organic layers were washed with brine and dried over magnesium sulfate. Removal of the solvent gave 56 mg, which was chromatographed on a silica gel column eluting with ethyl acetate: methylene chloride: methanol saturated with ammonia (2: 1: 0.03); This gives 18 mg (25%) of epibatidine (19), mp 50-51 ° C and 20 mg (28.4%) of endo-epibatidine (19 '). The spectral data for these compounds are shown in Table 3.

Table 3

Spectral data for epibatidine (19) and endo-epibatidine (19 ')

epibatidine (1 9) endo-epibatidine (19 ') MS (CI) m / z 209 211 (M + 1) 209 211 (M + 1) H ¹ NMR Hi, ₄₁ 3.80 (t, 3.9 Hz), 3.56 (wide s) 3.76 (q, 4.8 Hz) H _3e 1.90 (dd, 12.0, 9.0 Hz) 2.12 (tdd, 12.3, 4.8, 3.3 Hz)

yl

The N-acetyl derivative of epibatidine is prepared by treating epibatidine with acetic anhydride in the presence of triethylamine. Like the other N-substituted 7-azabicyclo [2.2.1] heptane derivatives described in Example 31, the free amine is deprotected. The amine derivatives can be acylated to amides, alkylated to give a tertiary amine derivative, and quaternary ammonium derivatives can be prepared by conventional methods. Amine compounds form stable, water-soluble salts with organic or inorganic acids, which are preferably used in pharmaceutical compositions.

Example 33

Preparation of 7-Methoxycarbonyl-2- (2-methoxypyridyl) -7-azabicyclo [2.2.1] heptane (29) mg of 7-methoxycarbonyl 1-2- (2- k-r-5-pyridyl) -7-aza-bi-k io [2.2.1] heptane is dissolved in 1.0 ml of methanol containing 12.8 mg (0.2 mmol) of potassium hydroxide. After stirring for 1 hour, the mixture was concentrated and partitioned between ethyl ether and water. The aqueous phase was re-extracted with ether and the combined organic layers were washed with saturated sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. Removal of the solvent gave 10 mg of a residue. ¹ H NMR data indicates that the resulting material contains a 1: 2 mixture of exo and endo isomers. 1 H-NMR 3.92, 3.90 (2s, Py-OCH ₃ ), 3.71, 3.66 (2s, NCOOCH ₃ ).

yl

Example 34

Preparation of epibatidine dichloro analogs (30) mg N-methoxycarbonyl-5- (2-chloro-5-pyridyl) -7-azabicyclo [2.2.1] hept-2-ene 25 mg 7% 10%. of activated charcoal palladium in 3 ml of methanol. The mixture was hydrogenated under a slight hydrogen pressure for 1 hour. The catalyst and solvent were removed and the residue was partitioned between ether and aqueous sodium bicarbonate. The aqueous phase is extracted with ether and the combined organic phases are dried over anhydrous magnesium sulfate. Removal of the solvent afforded 10 mg of 7-methoxycarbonyl-2- (3-pyridyl) -7-azanorbornene (12).

MS (CI) m / z 233 (M + 1). 1 H-NMR 3.72, 3.66 (2s, N-COOCH ₃ ).

Example 35

Preparation of 5,6-dehydro analogs of epibatidine

The N-acylated 7-azabicyclo [2.2.1] hept-5-ene prepared according to Example 30 was subjected to acid hydrolysis under the conditions described in Example 32 to give the 5,6-dehydro derivatives of epibatidine (19). ) and their endo-isomers (19 ').

/ 1

Example 36

Preparation of 1,4-Dimethyl-2- (6-chloro-3-pyridyl) -3-phenylsulfonyl-7-methoxycarbonyl-7-azabicyclo [2.2.1] hept-2,5-diene

A mixture of 0.14 g (0.5 mmol) of 2-chloro-5-pyridyl-phenylsulfonylacetylene (22) and 0.7 g of 2,5-dimethyl-N-methoxycarbonylpyrrole (31) was heated for 48 hours. the temperature was maintained at 85 ° C. Excess paper (31) was removed in vacuo and the dark residue was purified by chromatography on silica gel eluting with 25-33% ethyl acetate in petroleum ether; 76 mg (35%) of the title compound are obtained. MS (CI) m / z 431, 433 (M + 1).

1 H-NMR 6.79, 6.55 (AB, J = 5.4 Hz, H _{5 6} ), 3.52 (s, 3H, N-COOCH ₃ ), 1.96, 1.68 (2s, 6H 2 CH ₃ ).

Example 37

Preparation of benzoyl-phenylsulfonyl-methane (32)

The procedure is carried out as described for the preparation of compound 20. The title compound is obtained in 60% yield as a white crystalline product, crystallization from carbon tetrachloride. M.p. 91-93 ° C (literature, m.p. 93-94 ° C).

Suitably substituted keto-sulfone derivatives are obtained when 4-chlorobenzoic acid, 3-methoxybenzoic acid, 3,4-methylenedioxybenzoic acid, 3,4,5-trimethoxybenzoic acid, 3-trifluoro is substituted for benzoyl chloride methyl benzoic acid, 3-dimethylaminobenzoic acid, 4-methylthiobenzoic acid, 4-methylsulfinylbenzoic acid, 4-methylsulfonylbenzoic acid, 3,5-difluorobenzoic acid,

The acid chloride of 2-naphthoic acid, 4-dimethylamino-2-naphthoic acid, 6-methoxy-2-naphthoic acid, 2-phenylpropionic acid or 2- (3,4-methylenedioxyphenyl) propionic acid is used.

Example 38

Preparation of phenyl (phenylsulfonyl) acetylene (34)

The procedure was carried out as described in Example 22. The crude product was purified by chromatography on silica gel using 5% ethyl acetate in petroleum ether as eluent to give the title compound as a solid in 20% yield.

Proceeding as above, but employing the other ketosulfone derivatives described in Example 37, they can be converted to the appropriately substituted aryl and aralkylacetylene derivatives.

Example 39

Preparation of 7- (methoxycarbonyl) -2-phenyl-3- (phenylsulfonyl) -7-azanorborna-2,5-diene (35)

Phenylsulfonylacetylene 34 (84.3 mg, 0.35 mmol) was treated with N-methoxycarbonylpyrrole (21) (0.42 g). The mixture was heated at 85 ° C for 48 hours. Excess pyrrole was removed and the residue was chromatographed on a silica gel column using 25-33% ethyl acetate in petroleum ether; This gave 30 mg (23%) of the adduct as a colorless oily product.

MS (CI) m / z 368 (M + 1).

¹ H-NMR 7.05 (s, 2H, H _{5 6} ); 5.51, 5.48 (2s, 2H, H _{1> 4),} 3.5 (br s, 3H, _N-COOCH3).

Proceeding as above, but subjecting the substituted pyrrole derivatives described in Example 28 and the substituted acetylene derivatives described in Example 38, undergoes cycloaddition to provide the corresponding 7-azabicyclo [2.2.1] hepta-2,5-diene adduct.

Example 40

Preparation of 2-phenyl-7-azabicyclo [2.2.1] heptane (36)

Bicyclic adduct 35 is reductively desulfonated, hydrogenated and then hydrolyzed under acidic conditions as described in Examples 30, 31 and 32 to afford the title compound 36. Similarly, the other bicyclic adduct derivative described in Example 39 can be converted, as described above, into the corresponding 2-substituted aryl-7-azabicyclo [2.2.1] heptane.

Example 41

Preparation of 2-phenyl-7-azabicyclo [2.2.1] hept-5-ene (37)

Bicyclic adduct 35 is reductively desulfonated and hydrolyzed under acidic conditions as described in Examples 30 and 32 to afford the title compound 37. Similarly, the other bicyclic adduct described in Example 39 may be converted to the corresponding 2-substituted aryl-7-azabicyclo [2.2.1] hept-5-ene.

* · »«

Example 42

Preparation of 5- and / or 6-substituted 2-aryl (or heteroaryl) -7-azanorbornane derivatives of the corresponding 7-N-acyl or 7-aza-2-aryl (or heteroaryl) -norborn-5-ene- derivatives

The 5 and / or 6 substituents are introduced into the compound by subjecting the 5,6-position double bond to known reactions such as addition, treatment with borohydrogen, epoxidation followed by a nucleophile (alkoxide, amine, azide). , alkyl sulfide, halide or hydroxide, and so on).

Example 43

Preparation of 3-Methyl-7-aza-2-exo- (2-chloro-5-pyridyl) bicyclo [2.2.1] heptane (38)

7-Methoxycarbonyl-2- ^z 2-chloro-5-pyridyl) -3- (phenylsulfonyl) -7-azabicyclo [2.2.1] hept-2,5-diene (23) in methanol containing 10% palladium on carbon hydrogenation until the double bonds are saturated. The resulting 7-carbonylmethoxy-2- (2-chloro-5-pyridyl) -3-phenylsulfonyl-7-azabicyclo [2.2.1] heptane (39) was dissolved in anhydrous tetrahydrofuran and the solution was stirred at -30 ° C. After treatment with N-butyllithium (1.1 equivalents) at a temperature of from 0 to 0 ° C, a solution of 1.1 equivalents of methyl iodide in tetrahydrofuran is added. The reaction mixture was stirred at room temperature and then poured into ice water. The mixture is extracted with ether and the organic phase is washed with water. The ethereal solution was dried and concentrated, and the crude product was chromatographed on a silica gel column using petroleum ether / ethyl acetate (3: 1); This gives the stereoisomers of 7-carbonylmethoxy-2- (2-chloro-5-pyridyl) -3-methyl-3-phenylsulfonyl-7-azabicyclo [2.2.1] heptane (40). As described in Example 30, the alkylated product was treated with sodium amalgam to remove the phenylsulfonyl group from the compound, followed by acidic treatment of the 7-carbonylmethoxy group as described in Example 32 to give compounds 8 and 8 '. Isomeric forms of its 3-methyl derivatives are obtained.

When ethyl bromide, allyl bromide, benzyl chloride, methoxymethyl chloride or methoxyethyl methanesulfonate is used instead of methyl iodide, the corresponding 3-ethyl, 3-allyl, 3-benzyl , 3-methoxymethyl or 3-methoxyethyl.

The other 2-aryl or 2-heteroaryl derivative of the other 7-N-acyl-7-aza-3-phenylsulfonylbicyclo [2.2.1] hepta-2,5-diene described in Example 29 was similarly hydrogenated to give the compound. conversion to the corresponding sulfonylcarbanion, alkylation, desulfonation and deacylation affords the corresponding 3-alkyl or aralkyl derivatives.

Example 44

Preparation of 7-methyl-7-aza-2-exo- (2-chloro-5-pyridyl) bicyclo [2.2.1] heptane (41)

Epibatidine 19 prepared according to Example 32 is alkylated with 1.1 equivalents of methyl iodide in tetrahydrofuran at room temperature and then worked up in the usual manner to give the 7-N-methyl derivative.

Similarly, alkylation with ethyl iodide, isopropyl bromide, allyl bromide, cyclopropylmethyl bromide, benzyl chloride, 4-methoxybenzyl chloride, 3,4-dimethoxybenzyl chloride, phenethyl bromide, propargyl bromide with hydroxyethyl chloride or methoxyethyl iodide to give the corresponding 7-N-alkylated derivative.

Alkylation of the other substituted 7-azabicyclo [2.2.1] heptane as starting material gives the corresponding 7-N-alkyl derivative.

The N-acetyl derivative of epibatidine of Example 7 can be reduced to the N-ethyl derivative by treating the N-acetyl compound with lithium aluminum hydride at room temperature in anhydrous tetrahydrofuran; similarly, by reducing the 7-N-propionyl, Ν-benzoyl, N-phenylacetyl and Ν-2-furoyl derivatives of epibatidine, the corresponding 7-propyl, 7-benzyl, 7-phenethyl, and 7 - (2-furfuryl) derivative.

Example 45

Resolution of racemic compounds

The 7-azabicyclo [2.2.1] heptane derivatives may be separated into their optical isomers by conventional means; these methods include chiral column chromatography, fractional recrystallization of diastereomeric salts of optically active acids, and / or

isolation of optically active esters or amides followed by recovery of optically pure enantiomers, see Monograph Optical Resolution Procedures for Chemical Compounds, Volume 1, Amines; Newman P., Optical Resolution Information Center, N.Y. 10471 (1980)].

Example 46

Resolution of racemic epibatidine (19)

To a methylene chloride solution containing racemic epibatidine (19) and 1.1 equivalents of triethylamine is added 1.1 equivalents of (-) - chloroformate menthyl ester. The reaction mixture was stirred at room temperature for 6 hours, washed with ice water and then dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was chromatographed on a silica gel column using petroleum ether / ethyl acetate (5: 1); Thus, the 7-N - (-) - menthyloxycarbonyl derivative of D- and L-epibatidine is obtained in the form of a mixture of two diastereomers. The diastereomers were separated by HPLC on an optically active packed column, each isomer treated with HBr / AcOH as described in Example 32; This gives the corresponding d and i-epibatidine.

Example 47

Preparation of optically active isomers of substituted 7-azabicyclo [2.2.1] heptane derivatives starting from optically active intermediates

Proceeding as described above, N-carbo- (-) - menthyloxypyrrole was prepared from pyrrole and (-) - chloroformate menthyl ester. The optically active pyrrole is treated with sulfonyl acetylene 22 or 34 as described in Example 29 to give a diastereomeric mixture of the optically active cycloadduct of the 7-azabicyclo [2.2.1] hepta-2,5-diene derivative. The resulting mixture was treated with sodium amalgam as described in Example 30 to give a diastereomeric mixture of 2-exoaryl-7-azabicyclo [2.2.1] hepta-5-ene. The diastereomers are separated by chromatography to give the d- and 1-enantiomers. The optically active intermediates are reduced and treated with HBr / AcOH to give optically active epibatidine enantiomers. In a similar manner, another substituent 7-azabicyclo [2.2.1] heptane is obtained starting from the corresponding optically active pyrrole derivative and optically active cycloadduct.

Example 48

Preparation of benzo [5a, 6a] epibatidine (39)

The preparation of compound 39 is illustrated in Scheme 4.

(a) Preparation of N-methanesulfonylisoindole (40)

0.88 g of sodium hydride is suspended in 3 ml of dimethylformamide. A solution of methanesulfonamide (0.95 g, 10 mmol) in dimethylformamide (5 mL) was added dropwise to the solution while stirring under nitrogen. The mixture was stirred at 60 ° C for half an hour and then added to the solution

A solution of α, α'-dibromo-o-xylene (2.64 g, 10 mmol) in dimethylformamide (7 mL) was added at such a rate as to maintain the temperature of the mixture at 60-70 ° C. The beginning ♦ »«

After stirring at room temperature for an additional hour, the reaction was quenched with water and quenched. The resulting precipitate was collected and washed with water, petroleum ether and ether. 1.57 g (80%) of the title compound are obtained.

¹ H-NMR δ 2.37 (s, 3H, -CH ₃ ); 4.709 (s, 4H, 2CH _2), 7.25 ~ 7.35 (m, 4H, Ar).

b) Preparation of 2- (6-Chloro-3-pyridyl) -3- (phenylsulfonyl) -1,4-dihydronaphthalene-1,4-imine (41)

Potassium tert-butoxide (560 mg, 5.0 mmol) was dissolved in dimethylsulfoxide (3 mL) under nitrogen. To the solution, while stirring, was added N-methanesulfonylisoindole (197 mg, 1.0 mmol) in portions. After the addition was complete, the mixture was stirred at room temperature for 1.5 hours and quenched with water (3 mL). Extract with ether (45 mL), wash the combined organic layers with brine, and dry over anhydrous magnesium sulfate for 10 minutes. The organic layer was filtered and the filtrate was treated with 1- (6-chloro-3-pyridyl) -2-phenylsulfonylacetylene (22) (83 mg, 0.3 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated in vacuo and chromatographed on a silica gel column. Elution was carried out with a mixture of ethyl acetate, methylene chloride and methanol containing ammonia; 108 mg of a blue residue are obtained. The resulting colorless material was washed with acidic water, basified and extracted with ether; 62 mg (41) of a colorless compound are obtained in the form of a foam-like product. Yield: 52%; MS (Cl), 395. 397 (M + 1).

¹ H-NMR (CDCl ₃ ) δ 5.242 (d, J = 1.5 Hz, 1H), 5.362 (d, J = 0.9 Hz, 1H), (H or H ₄ ).

c) Preparation of exo and endobenzo [5a, 6a] epibatidine (39) Compound 41 (0.137 mmol) was dissolved in a mixture of methanol (3 mL) and tetrahydrofuran (1 mL). The solution was cooled to -20 ° C and 66 mg of 6% sodium amalgam was added. The mixture was stirred for 2 hours. The excess reagent is quenched by addition of water and the liquid phase is decanted. The liquid was concentrated in vacuo and the residue was extracted with methylene chloride (3 x 5 mL). The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was separated by thin layer chromatography using 33% methylene chloride in ethyl acetate; 5.5 mg of exo-benzo [5a, 6a] epibatidine and 8.5 mg of endo-benzo [5a, 6a] epibatidine are obtained. Both isomers are obtained in the form of an oily product. Yield values: 15% and 25% respectively.

MS (Cl), 257, 259 (M + 1).

¹ H-NMR (CDCl ₃ ) (exo isomer) 2.753 (dd, J = 4.8, 8.4 Hz, 1H, H ₂ ), 4.371 (s, 1H, H), 4.656 (d, J = 4 Hz) , 1H, H _4).

• ·· · • · · · · 4 il

- 78 Example 49

Preparation of N-methylbenzo [5a, 6a] epibatidine (42)

The preparation of N-methylbenzo [5a, 6a] epibatidine (42) is described in Figure 5.

illustrates the reaction scheme.

a) Preparation of N-methylisoindole (43)

N-methyl isoindole was prepared as described in the literature (Zeeh, B. and König, K. H., Synthesis, 45, 1972).

b) Preparation of 2- (6-Chloro-3-pyridyl) -3- (phenylsulfonyl) -1,4-dihydronaphthalene-1,4-imine (44) mg (0.7 mmol) of N-methylisoindole 139 1- (6-chloro-3-pyridyl) -2-phenylsulfonylacetylene (22 mg, 0.5 mmol) in ethyl ether. The mixture was stirred at room temperature for 1 hour and then chromatographed on a silica gel column eluting with ethyl acetate. 204 mg of compound 44 are obtained in the form of a pure oily product.

Yield: 100%.

MS (Cl), 409, 411 (M + 1).

1 H-NMR (CDCl ₃ ) δ 2.36 (broad, 3H, NCH ₃ ), 4.805 (s, 1H); 4.93 (br s, 1H), (HI, or F _4).

c) Preparation of N-methyl I-benzo [5a, 6a] epi ba thidi n (42)

Compound 44 (125 mg, 0.306 mmol) was dissolved in a mixture of methanol (10 mL) and tetrahydrofuran (4 mL). After cooling to -20 ° C, 216 mg of sodium dihydrophosphate and 1.0 g of 6% sodium amalgam are added. The mixture was stirred at room temperature for 3 hours and quenched with water. The organic phase is decanted and then concentrated in vacuo. The residue was extracted with methylene chloride (2 x 10 mL). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was chromatographed on a silica gel column using 50% ethyl acetate in petroleum ether as eluent. This gave 19 mg (19%) of exo-N-methylbenzo [5a, 6a] epibatidine. Further elution with ethyl acetate, methylene chloride and methanol containing ammonia gave 55 mg (66%) of the endo isomer. Total yield: 85%.

MS (Cl), 271, 273 (M + 1).

¹ H-NMR (CDCl ₃ ) (exo isomer): 2.679 (dd, J = 4.5, 8.7 Hz, 1H, H ₂ ), 3.935 (s, 1H, H 1); 4.203 (d, J = 4.0 Hz, 1H, H _4), 2072 (s, 3H, _NCH3).

Example 50

Preparation of N-formamidinyl-epibatidine dihydrochloride (45)

The preparation of the compound of formula 45 is illustrated in Scheme 6.

Racemic epibatidine (19) (19 mg) (0.2 mmol) was combined with freshly prepared formamide ethyl ester hydrochloride (77 mg, 0.7 mmol) and diisopropylethylamine 129 mg (1.0 mmol) in 1 mL of acetonitrile. After stirring at room temperature for 48 hours, the reaction mixture was acidified with 1.0 M ethereal HCl. The mixture was concentrated in vacuo and the residue was separated by preparative thin layer chromatography using silica gel and 25% methanol in chloroform as solvent; 25 mg of the title compound are obtained as a hygroscopic solid. Yield: 36%.

MS (Cl), 236, 238 (M + 1 free base).

¹ H-NMR (CD ₃ OD) δ 3.40 (Μ, 1H, H ₂ ).

Example 51

Proceeding as in Example 50, but using S-methyl-pseudothiourea, S-methyl-N-methyl-pseudothiourea, S-methyl-N-nitro-pseudothiourea or acetic acid-methyl-methyl instead of the formamidine ethyl ester used therein. N-guanidyl, β-methyl guanidyl, N-nitroguanidyl or N-acetamidinyl epibatidine can be prepared.

Example 52

Preparation of N-formamidinyl dechlorepibatidine dihydrochloride (46) Dissolve mg (0.04 mmol) of N-formamidinyl epibatidine (45) in 2 ml of methanol containing 5 mg of palladium on carbon. Under 1 atmosphere of hydrogen, the mixture was hydrogenated for 3 hours, after which the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 10 mg of compound 46 as a hygroscopic solid. Yield: 100%.

MS (Cl), 202 (M + 1 - 2HCl).

yl

- 81 ¹ H-NMR (CD ₃ OD) δ 3.5 (Μ, 1 Η, Η ₂ ).

Example 53

Preparation of 1-methyl-epibatidine (47) and 4-methyl-epibatidine (48)

a) Preparation of 2-methylpyrrole (49)

The preparation of 2-methylpyrrole is carried out as described in the literature [J. Org. Chem. 28, 3052].

b) Preparation of N-tert-butoxycarbonyl-2-methylpyrrole (50)

Dissolve 2.5 g of 2-methylpyrrole in 6 ml of tetrahydrofuran and add the resulting solution slowly to a suspension of 2.4 g of 60% sodium hydride (washed in ether) in 30 ml of tetrahydrofuran. To the cooled mixture was added a solution of 7.6 g of di-tert-butyl dicarbonate in 20 ml of tetrahydrofuran. The mixture is shaken occasionally, and after 3 hours, water is added to quench the reaction, followed by extraction with ether. The combined organic layers were washed with brine and then dried over magnesium sulfate. Removal of the solvent gave 6 g of a residue. Distillation on a ball-cooler gave 4.5 g of a pale yellow oily product (80 ° C / 6.66 x 10 ² Pa). Yield: 80%.

MS (Cl), 183 (M + 2).

¹ H-NMR (CDCl ₃ ) δ 1.584 (s, 9H, 3CH ₃ ), 2.421 (s, 3H,

CH ₃ ).

• ··

ii

- 82 Preparation of 1 (and 4) -methyl-2- (6-chloro-3-pyridyl) -3-phenylsulfonyl-7-tert-butoxycarbonyl-7-azanorborna-2,5-diene (51)

Compound 50 (1.8 g, 10 mmol) was added with 1- (6-chloro-3-pyridyl) -2-phenylsulfonylacetylene (22) (555 mg, 2.0 mmol) in a tightly closed flask with nitrogen gas. while maintaining at 78 ° C for 24 hours. The mixture was separated on a silica gel column using 25% ethyl acetate in petroleum ether as eluent.

Obtaining 1.5 g of compound 50 and 120 mg of compound 22 affords 636 mg of compound 51 as a yellow oil. Yield: 69.3%. According to ¹ H-NMR data of the oily product of 2-methyl-1-methyl isomer and 4-isomer: 1 mixture of.

MS (Cl), 459, 461 (M + 1).

¹ H-NMR (CDCl ₃ ) (to the higher isomer): 1.37 (s, 9H, 3CH ₃ ); 1.748 (s, 3H, CH ₃ ); 5.45 (d, J = 3 Hz, 1H, H _4), (present in minor isomer): 1.346 (s, 9H, 3CH _3); 1.958 (s, 3H, CH ₃ ); 5.26 (d, 1H, J = 3Hz, HI).

d) Preparation of N-tert-Boc-1 (and 4) -methyl-epibatidine (52)

Compound 51 (459 mg, 1.0 mmol) was dissolved in a mixture of methanol (20 mL) and tetrahydrofuran (10 mL). The solution was stirred and cooled to -20 ° C. To this solution was added 720 mg of sodium dihydrophosphate followed by 1.5 g (6.0 mmol) of 6% sodium amalgam. After stirring at room temperature for 2 hours, 0.8 g of 6% sodium 83-amalgam was added and stirring was continued for a further 2 hours. The excess reagent was quenched with water and the solution decanted. The solution was concentrated in vacuo at room temperature and the residue was extracted four times with 15 ml of methylene chloride. The combined organic phases were washed with brine and dried over magnesium sulfate. After removal of the solvent, the resulting residue (372 mg) was hydrogenated at atmospheric pressure in the presence of platinum oxide (8.4 mg) for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to give 360 mg of a residue. The residue was purified on a silica gel column eluting with 17% ethyl acetate in petroleum ether. 95 mg of endo-isomer and 65 mg of exo-isomer are obtained. Total yield: 50%. MS (Cl), 323, 325 (M + 1). ^1H-NMR _(CDCl3) (present in the larger amount of exo isomer): 2.78 (dd, 1H, J = 5.4 Hz, 7.8 Hz, ₂ H), 4.45 (t, 1H, J = 4.5 Hz, H ₄ ).

e) Preparation of 1-methyl-epibatidine (47) and 4-methyl-epibatidine (48) mg of the exo isomer of compound 52 was dissolved in 5 ml of methylene chloride. The solution was cooled to 0 ° C and then cooled

Trifluoroacetic acid (2.5 mL) was added. The resulting pink solution was then stirred at room temperature for 1.5 hours. A solution of 4.5 g of potassium carbonate in 10 ml of water is neutralized, the organic phase is separated off and the aqueous phase is extracted with methylene chloride. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin layer chromatography using a mixture of ethyl acetate, methylene chloride and methanol containing ammonia; 6 mg of 4-methyl-epibatidine (48) and 12 mg of 1-methyl-epibatidine (47) are obtained. Yield: 40.2%.

MS (Cl), 223, 225 (M + 1).

¹ H-NMR (CDCl ₃ ) (1-methyl-epibatidine, higher exo isomer) δ 2.657 (dd, J = 4.8, 8.7 Hz, 1H H ₂ ), 3.694 (t, J = 4.7 Hz, 1H, H _4).

(4-Methyl-epibatidine, minor exo isomer): 2.887 (dd, J = 4.7 Hz, 1H, H ₂ ), 3.486 (d, J = 4.5 Hz, 1H, H _{1 t} )

Example 54

Preparation of 2- (2-Fluoro-5-pyridyl) -7-azanorbornane (53) a) Preparation of 1- (2-Fluoro-5-pyridyl) -2-phenylsulfonylethanone (54)

The procedure described in Example 26 was followed except that the 6-chlorinated time mentioned therein was replaced with 6-fluoronicotinyl chloride (Anderson et al., J. Med. Chem.). ., 33 (6), 1667 (1990)]; compound 54 was obtained as a white crystalline product; mp 127-128 ° C. Yield: 72%.

MS (Cl), 280 (M + 1).

¹ H-NMR (CDCl ₃ ) δ 2.70 (s, 2H, CH ₂ ).

b) Preparation of 1- (2-Fluoro-5-pyridyl) -2- (phenylsulfonyl) acetylene (55)

By following the procedure described in Example 27, the

Compound 55, starting from Compound 54; The title compound was obtained as a white solid in 62% yield. Melting point: 97-98.5 ° C. MS (CI) 262 (M + 1).

c) Preparation of 7-Methoxycarbonyl-2- (2-fluoro-5-pyridyl) -3-phenylsulfonyl-7-azabicyclo [2.2.1] hepta-2,5-diene (56)

The same procedure as in Example 29 was used, starting from the acetylene derivative 55; The title compound was obtained as a white crystalline product in 66% yield, and 22% of the starting compound was recovered. 85-87 ° C.

MS (CI) 387 (M + 1).

¹ H-NMR (CDCl 3) δ 3.446 (bs, 3H, CH ₃ ), 5.459 (d, J = 7.2 Hz, 2H, H ₁₄ ).

d) Preparation of 7-Methoxycarbonyl-5- (2-fluoro-5-pyridyl) -7-azabicyclo [2.2.1] hept-2-ene (57)

The procedure described in Example 30 was followed, however, starting from compound 56; The product 57 is obtained in the form of a 1: 2.5 mixture of exo and endo isomers; overall yield: 64%. MS (CI) 249 (M + 1).

¹ H NMR (CDCl ₃ ) (endo-isomer data) 3.682 (s, 3H, OCH 3);

(data for exo-isomer), 3.655 (s, 3H, OCH ₃ ).

e) Preparation of 7-Methoxycarbonyl-2- (2-fluoro-5-pyridyl) -7-azabicyclo [2.2.1] heptane (58)

In the same manner as in Example 31, starting from compound 57, compound 58 was obtained as a colorless oily product; Yield: 93.3%.

MS (CI) 251 (M + 1).

¹ H-NMR (CDCl 3) (endo-isomer data) δ 3.722 (s, OCH 3), (exo-isomer data) δ 3.671 (s, 3H, OCH ₃ ).

f) Preparation of 2- (2-fluoro-5-pyridyl) -7-azanorbornane (53)

Example 32 was carried out using 185 mg of 58 (0.74 mmol) as starting material; This gave 23 mg (16.2%) of the exo-isomer of compound 53 and 54.8 mg (38%) of the endo-isomer of compound 53 as an oily product.

MS (CI) 193 (M + 1).

¹ H-NMR (CDCl 3) δ 2.763 (dd, J = 0.8, 9.0 Hz, 1H, H 2), 3.532 (s, 1H, H0, 3.769 (t, J = 3.6 Hz, 1H, H) ₄ ) (data for endo-isomer), δ 3.324 (dt, J = 12 Hz, 1H, H ₂ ), 3.779 (q, J = 5.1 Hz, 2H, Hi, ₄ ).

il • · ♦ V 4 ··· ♦ ·· · · «· ν · • · · J

Example 55

Preparation of 2- (2-Chloro-3-pyridyl) -7-azanorbornane (59)

a) Preparation of 1- (2-chloro-3-pyridyl) -2- (phenylsulfonyl) ethanone (60)

Example 26 was repeated using 2-chloronicotinyl chloride as starting material; The title compound was obtained in 74% yield as a white solid; mp 103-104 ° C.

MS (CI) 296, 297 (M + 1).

¹ H-NMR (CDCl 3) δ 4.871 (s, 2H, -CH ₂ -).

b) Preparation of 1- (2-Chloro-3-pyridyl) -2- (phenylsulfonyl) acetylene (61)

The procedure of Example 27 was followed, starting from compound 60; Yield: 27% as a white solid; 90-94 ° C.

MS (CI) 278, 280 (M + 1).

c) 7-Methoxycarbonyl-2- (2-chloro-3-pyridyl) -3- (phenylsulfonyl) -7-azabicyclo [2.2.1] hepta-2,5-diene (62) production

The procedure of Example 29 was followed, starting from compound 61; the title compound is obtained as an oily product.

MS (CI) 03, 405 (M + 1).

¹ H-NMR (CDCl ₃ ) δ 3.612 (s, 3H, OCH ₃ ); 5.429 (t, J = 2.1 Hz, 1H), 5.497 (t, J = 2.1 Hz, 1H).

··· · · ···

d) Preparation of 7-methoxycarbonyl-5- (2-chloro-3-pyridyl) -7-azabicyclo [2.2.1] hept-2-ene (63)

Following the procedure of Example 30, the title compound was obtained, in the form of 12% exo-isomer and 35% endo-isomer.

MS (CI) 265, 267 (M + 1).

¹ H-NMR (CDCl 3) (exo-isomer) δ 3.66 (s, 3H, OCH ₃ ); 6.502 (br s, 2H, Hs.e), ¹ H NMR (CDCl?) (Endo-isomer) δ 3.686 (s, 3H, _OCH3); 4.882, 5.029 (2s broad, 2H, H _14), 5.88, 6.544 (2s broad, 2H, H _5i6).

e) Preparation of 7-Methoxycarbonyl-2- (2-chloro-3-pyridyl) -7-azabicyclo [2.2.1] heptane (64)

The procedure described in Example 31 was followed by hydrogenation of the exo form of compound 63 to give the title compound in quantitative yield.

MS (CI) 267, 269 (M + 1).

¹ H-NMR (CDCl 3) δ 3.277 (dd, J = 4.5, 8.4 Hz, 1H, H ₂ ), 3.654 (s, 3H, OCH ₃ ).

f) Preparation of 2- (2-Chloro-3-pyridyl) -7-azanorbornane (59)

Following the procedure of Example 32, starting with the exo form of Compound 64, Compound 59 was obtained in 40% yield as an oily product.

MS (CI) 209, 211 (M + 1).

··· · · ···

- 89 ¹ H NMR (CDCl 3) δ 3.162 (dd, J = 4.8, 8.7 Hz, 1H, H 2), 3.681 (s, 1H), 3.795 (t, J = 3.6 Hz, 1H) , (H 1 _f H ₄ ).

Example 56

Preparation of 2- (2-Chloro-4-pyridyl) -7-azabicyclo [2.2.1] heptane (65)

a) Preparation of 1- (2-Chloro-4-pyridyl) -2- (phenylsulfonyl) ethanone (66)

The procedure described in Example 26 was followed, except that 2-chloro-isonicotinyl chloride (Anderson et al., J. Med. Chem. 33 (b), 1667 (1990)) was used with the 6-chloro-nicotinyl chloride mentioned therein. instead; The title compound was obtained as a white crystalline product in 51% yield; 124-125.5 ° C (methanol).

MS (CI) 296, 298 (M + 1).

b) Preparation of 1- (2-Chloro-4-pyridyl) -2- (phenylsulfonyl) acetylene (67)

Following the procedure of Example 27, starting with compound 66, the title compound was obtained as a white crystalline product in 54% yield; m.p. 78-79 ° C.

MS (CI) 278, 280 (M + 1).

c) Preparation of 7-Methoxycarbonyl-2- (2-chloro-4-pyridyl) -3- (phenylsulfonyl) -7-azabicyclo [2.2.1] hepta-2,5-diene (68)

Following the procedure of Example 29, starting with 67, 68% of the title compound is obtained in the form of a pale brown oily product.

MS (CI) 403, 405 (M + 1).

^1H-NMR _(CDCl3) δ 3.502 (br s, 3H, _OCH3), 5.420, 5.483 (25, 2H, H _14), 7.065 (s, 2 H, H _{fifth 6).}

d) Preparation of 7-methoxycarbonyl-5- (2-chloro-4-pyridyl) -7-azabicyclo [2.2.1] hept-2-ene (69)

In the same manner as in Example 30, starting material 68 was used, followed by desulfonation to give the title compound as a 1: 2 mixture of exo and endo isomers in 13.6% yield.

MS (CI) 265, 267 (M + 1).

¹ H-NMR (CDCl ₃ ) (endo-isomer) δ 3.682 (s, 3H, OCH ₃ );

(exo-isomer) δ 3.665 (s, 3H, OCH ₃ ).

e) Preparation of 7-Methoxycarbonyl-2- (2-chloro-4-pyridyl) -7-azabicyclo [2.2.1] heptane (70)

The procedure of Example 31 was followed, starting from compound 69; hydrogenation of this compound gave the title compound in 95% yield. MS (CI) 267, 269 (M + 1).

¹ H-NMR (CDCl ₃ ) (data for endo-isomers), δ 3,694 (s, 3H, OCH ₃ ), (data for exo-isomers): δ 3,655 (s, 3H, OCH ₃ ).

f) Preparation of 2- (2-Chloro-4-pyridyl) -7-azabicyclo [2.2.1] heptane (65)

Following the procedure of Example 32, starting with compound 70; deprotection of this compound afforded compound 65 (exo isomer) in 23.6% yield.

MS (CI) 209, 211 (M + 1).

1 H-NMR (CDCl ₃ ) δ 2.738 (dd, J = 9.0, 5.1 Hz, 1H, H ₂ ), 3.629 (d, J = 2.4 Hz, 1H), 3.791 (bs, 1H ).

A small amount of endo-isomer was isolated.

Example 57

Preparation of 7-Epibatidinyl phosphate disodium salt (71)

Dissolve 40.0 mg of epibatidine in 3 ml of phosphorus oxychloride and heat to reflux for 3 hours at room temperature. Excess reagent was removed in vacuo to give 100 mg of 7-epibatidinylphosphoryl dichloride as a brown oily residue. Dissolve 28 mg of the residue in 2 ml of tetrahydrofuran and add 2 ml of sodium hydroxide solution in an ice bath. The reaction mixture was stirred at room temperature for an additional 4 hours. After evaporation of the organic solvent, the aqueous solution was washed with ethyl ether (2 x 5 mL). The aqueous phase is then concentrated in vacuo to a volume of about 0.5 mL and the residue left at room temperature for several hours; The title compound is thus obtained in the form of a white crystalline product. Yield: 14 mg (80%).

¹ H-NMR (D ₂ O) δ 2.745 (p, J = 4.5 Hz, 1H, H 2), 3.723 (br s, 1H), 3.920 (br s, 1H), 7.357 (d, J = 8, 4 Hz, 1H), 8.073 (dd, J = 2.4, 8.4 Hz, 1H), 8.263 (d, J = 2.4 Hz, 1H).

³¹ P NMR (D ₂ O). 5.332.

By using chlorosulfonic acid or other N-sulfate reagents instead of phosphorus oxychloride and under the same reaction conditions, N-sulfate derivatives of epibatidine and analogs thereof can be prepared.

Example 58

Preparation of 2,3-dehydroepibatidine (72)

The preparation of compound 72 is illustrated in Scheme 7.

a) Preparation of 7-tert-Butoxycarbonyl-2- (2-chloro-5-pyridyl) -3-phenylsulfonyl-7-azabicyclo [2.2.1] hepta-2,5-diene (73)

In the same manner as in Example 29, starting from 1- (2-chloro-5-pyridyl) -2- (phenylsulfonyl) acetylene (22), this compound is treated with N-carbonyl-tert-butoxypyrrole. N-tert-Boc-pyrrole) under the conditions of the Diels-Alder reaction. The title compound was obtained as a white solid in 64% yield. M.p. 133-134 ° C. MS (CI) 445, 447 (M + 1).

b) Preparation of 7-tert-Boc-2- (2-chloro-5-pyridyl) -3- (phenylsulfonyl) -7-azabicyclo [2.2.1] hept-2-ene (73)

Adduct 73 (445 mg) was dissolved in a mixture of methanol (20 mL) and tetrahydrofuran (10 mL), containing 8 mg of platinum oxide. The mixture was hydrogenated under 1 atmosphere of hydrogen for 3 hours and then the catalyst was removed by filtration. The filtrate was concentrated in vacuo to give 440 mg of residue. The resulting material was triturated with methanol to solidify. Yield: 98%.

MS (CI) 447, 449 (M + 1).

¹ H-NMR (CDCl 3) δ 1.266 (s, 9H, C (CH ₃ ) ₃ ), 4.905, 4.945 (2 broad s, 2H, H 2 4.4).

c) Preparation of 2- (2-Chloro-5-pyridyl) -3- (phenylsulfonyl) -7-azabicyclo [2.2.1] hept-2-ene (75)

53e. Example 7, starting with compound 74, the tert-Boc protecting group was readily cleaved with trifluoroacetic acid at 0 ° C; The title compound was obtained in 95.4% yield as a white solid.

MS (CI) 347, 349 (M + 1).

¹ H-NMR (CDCl ₃ ) δ 4.423 (d, J = 4.2 Hz, 1H), 4.500 (d, J = 3.6 Hz, 1H), ( _H211 ).

yl

d) Preparation of 2,3-Dehydroepi bati di η (72)

365 mg of compound 75 were desulfonated under the conditions described in Example 30 to give 23 mg of the title compound as a colorless oily product. Yield: 19%.

MS (CI) 207, 209 (M + 1).

¹ H-NMR (CDCl ₃ ) δ 4.323 (s, 1H, H 2, 4.574 (d, J = 3.0)

Hz, 1H, H _4), 6.560 (d, J = 2.4 Hz, 1H, H _3).

Example 59

Preparation of chloroethyl epibatidine (76)

Under the conditions described in Example 44, epibatidine 19 was used as a starting material and was alkylated with 1-chloro-2-bromoethane in 35% yield to give the title compound as a pure oil.

MS (CI) 271, 273, 275 (M + 1).

1 H-NMR (CDCl ₃ ) δ 3.225, 3.476 (25, 2H, H ₁₄ ), 3.568 (t, J = 6.6 Hz, 2H).

Example 60

Preparation of 2- (2-Hydroxy-5-pyridyl) -7-azanorbornane (77)

Compound 53 (8.5 mg, 0.044 mmol) was dissolved in t-butanol (1 mL). To this solution was added 1 ml of 2N potassium hydroxide. The mixture was refluxed for 20 hours and then the butanol was distilled off; adjust the pH of the mixture to 6-7 with 1 N hydrochloric acid. The solvent was removed in vacuo and the resulting product was purified by preparative thin layer chromatography; silica gel eluting with 20% methanol in chlorol form (where methanol has an ammonia content of 7 n); 4.2 mg of the title compound are obtained in the form of an oily product. Yield: 50%. MS (CI) 191 (M + 1).

¹ H-NMR (CDCl ₃ ) δ 2.554 (bs, 1H, H ₂ ), 3.503; 3,473 (2 broad s, 2H, H ₁₄ ) ·

Example 61

Preparation of 2- (2-Methylthio-5-pyridyl) -7-azanorbornane (78)

Following the procedure of Example 33, starting with sodium methyl mercaptanide, the title compound was obtained as a colorless oily product in 28% yield.

MS (CI) 221, 223 (M + 1).

¹ H-NMR (CDCl 3) δ 2.542 (s, 3H, SCH ₃ ); 2.757 (dd, J =

5.1, 8.7 Hz, 1H, H ₂ ), 3.546, 3.781 (2 broad s, 2H, H ₁₁ ).

Example 62

Preparation of 5,6-bis (trifluoromethyl) -declorepibatidine (79)

The preparation of compound 79 is illustrated in Scheme 8.

a) Preparation of 7-tert-Boc-1,2-bis (trifluoromethyl) -7-azabicyclo [2.2.1] hepta-2,5-diene (80)

The title compound was prepared according to the method of Leroy J. et al., Synthesis, 313 (1982).

(b) Preparation of 7-tert-Boc-2,3-bis (trifluoromethyl) -5-pyridyl-7-azabicyclo [2.2.1] hept-2-ene (81)

165 mg (0.5 mmol) of compound 80 and 105 mg (0.5 mmol)

3-Iodopyridine is dissolved in 1 ml of dimethylformamide, which contains 9 ml of palladium acetate, 21 ml of triphenylphosphine, 120 mg of piperidine and 60 mg of 88% formic acid. The mixture was then stirred at 60-70 ° C under nitrogen for 1.5 hours and then at room temperature overnight. The solvent was removed in vacuo and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed in vacuo and the resulting residue (218 mg) was purified on a silica gel column using 20% ethyl acetate in petroleum ether as eluent; 48 mg of compound 81 are obtained in the form of a red oily product.

MS (CI) 409 (M + 1).

Yield: 23%.

1 H-NMR (CDCl ₃ ) δ 1.427 (s, 9H, OC (CH ₃ ) ₃ ); 2,974 (dd, J =

4.2, 8.4 Hz, 1H, H ₂ ), 4.906, 5.147 (2 broad s, 2H, H ₁₄ ).

Proceeding as described above, but employing 2-chloro-5-iodo-pyridine in place of the iodo-pyridine used, the corresponding 5- (2-chloro-5-pyridyl) -an analogue is obtained.

c) Preparation of 2,3-Bis (trifluoromethyl) -5-pyridyl-7-azabicyclo [2.2.1] hepta-2-ene (82)

In the same manner as in Example 53e, starting with compound 81, trifluoro97

treatment with acetic acid to remove the protecting group to give the title compound in 90% yield.

¹ H NMR (CDCl ₃ ) δ 2.02 (dd, J = 8.4, 2.1 Hz, 2H, H ₃ ), 2.88 (dd, J = 4.8, 8.4 Hz, 1H , H ₂ ), 4.36, 4.63 (2 broad s, 2H, H _11-14 ).

As described above, the 5- (2-chloro-5-pyridyl) analog is obtained.

d) Preparation of 5,6-bis (trifluoromethyl) dichloro-epibatidine (79)

Hydrogenation of Compound 82 under high hydrogen pressure gave the title compound.

Proceeding as above gives 5,6-bis (trifluoromethyl) epibatidine.

ARC. Medicinal preparations

Human patients, mammals such as horses, rabbits, cattle and other animals can be treated for pain by administering an effective amount of the compounds of the present invention or pharmaceutically acceptable salts thereof in admixture with pharmaceutically acceptable excipients and carriers. The active ingredient may be administered by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously or topically, in the form of a liquid, cream, gel or solid product.

The term pharmaceutically acceptable salts and complexes as used herein refers to salts and complexes which retain the biological activity of the compounds of the present invention while exhibiting minimal undesirable toxicological activity. Examples of such salts include, but are not limited to: (a) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, or the like, including organic acid salts thereof; among these are acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, naphthalene disulfonic acid, and polygalacturonic acid; (b) basic addition salts formed with metal cations, including zinc, calcium, bismuth, barium, magnesium, aluminum, copper, cobalt, nickel, cadmium, sodium, potassium and the like, with an ammonium, cation, Salts with? -Dibenzylethylenediamine, D-glucosamine, tetraethylammonium, and ethylenediamine; (c) a combination of addition salts of (a) and (b), such as zinc tannate addition salt, and so on.

The active ingredient of the present invention is admixed with pharmaceutically acceptable excipients and carriers in an amount such that a therapeutically effective amount can be administered to the treated patient without causing toxic effects to the treated patient. A preferred daily dose of the active ingredient is from about 0.0001 to about 20 mg / kg, preferably from about 0.001 to about 2 mg / kg, and usually from about 0.05 to about 0.5 mg / kg of body weight per day. Typical doses for topical administration are 0.001% to 0.5% by weight of the total formulation, in admixture with a suitable vehicle. The effective dose of the pharmaceutically acceptable derivative is calculated based on the weight of the patient treated with the parent compound. In the case where the derivative itself is effective, the weight of the effective dose is calculated based on the weight of the derivative or by other methods known to those skilled in the art.

The active ingredient is conveniently administered in a suitable dosage unit; For example, without limitation, the dosage unit may contain from 0.001 to 1000 mg, preferably 0.01 to 500 mg, of the active ingredient. Generally, for oral administration, the dose will be in the range of 0.1 to 200 mg.

The active ingredient may also be administered by intravenous injection, in which case the active ingredient may be in the form of a solution, preferably saline, or an aqueous medium, or the active ingredient may be administered in the form of a bolus.

The concentration of the active ingredient in a pharmaceutical composition depends on its absorption, distribution, inactivation and rate of drug excretion, as well as other factors well known to those skilled in the art. It is noted that the dose value also depends on the severity of the patient's condition. For each patient being treated, the dosage and dosage regimen will be adjusted to the individual need, and the dosage administered will be determined by the attending physician, with the concentration ranges mentioned herein

100, ι, therefore, are provided by way of example only and do not constitute limitations on the use of the particular preparation. The active ingredient may be administered once or in divided doses several times.

Compositions for oral administration generally contain an inert diluent or an edible carrier. The active ingredient may be formulated in gelatin capsules or compressed into tablets. For oral administration, the active ingredient is formulated in a tablet, dragee or capsule form with adjuvants, carriers. Compatible binders and / or adjuvants may be used to prepare the composition.

For the preparation of tablets, dragees, capsules, the following excipients may be used: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a carrier such as starch or lactose; a disintegrant such as alginic acid, primogel or corn starch; a lubricant such as magnesium stearate or Sterote, a lubricant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; flavoring agents such as peppermint mint, methyl salicylate or orange flavor. When the dosage unit form is a capsule, it may contain, in addition to the above excipients, a liquid carrier such as a fatty oil. In addition, the dosage unit may contain other substances which are physical in the dosage unit

101 </ g, such as sugar coatings, shellac, or other enteric agents.

The active ingredient of the invention, or a pharmaceutically acceptable salt or other derivative thereof, may also be used as a component of an elixir, suspension, syrup, chewing gum or other composition. Syrups may contain, in addition to the active ingredient, sucrose as a sweetening agent and preservatives, coloring agents and flavors.

The active compounds of the present invention and pharmaceutically acceptable derivatives or salts thereof may also be combined with other active ingredients which do not adversely affect the desired effect, or with substances which supplement the desired effect, such as antibiotics, antifungal agents, anti-inflammatory agents, and antiviral agents. agents.

Solutions for parenteral, intradermal, subcutaneous or topical administration may contain the following components: a sterile solvent such as water for injection, saline solution, stable oils, polyethylene glycols, glycerol, propylene glycol or other synthetic solvents. ; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, cyprates or phosphates; and agents for adjusting the isotonia of the solution, such as sodium chloride or dextrose. For parenteral use • · · il

Formulations 102 may be filled into ampoules, disposable syringes, multiple dose vials made of glass or plastic. In the case of preparations for intravenous administration, the carrier is preferably physiologically acceptable saline or phosphate buffered saline (PBS).

In one embodiment of the invention, the active ingredients may be supplemented with formulations that protect the active ingredient from being degraded too rapidly in the body to provide sustained release formulations, including implants, and a microcapsule release system. Biodegradable biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polyacetic acid may also be used. Methods for preparing these compositions are well known to those skilled in the art. The aforementioned excipients are commercially available (Alza Corporation).

V. Investigation of the analgesic activity of 7-azabicyclo [2.2.1] heptane and heptene derivatives

A wide variety of biological assays are used to check the analgesic effect of a compound. Any known assay may be used to monitor the analgesic activity of the compounds of the present invention. The Straub tail reaction typical of opium alkaloids is used to test for opium-type agonists and antagonists. A detailed description of this method can be found in the literature [Br. J. of • ·· «··

103

Pharmacol. 36, 225 (1969)]. Another commonly accepted assay for analgesic activity is the hot plate analgesic method [J. Pharmacol. Exp. Therap. 107: 385 (1953)]. An assay is also known in the literature for determining the ability of a given compound to bind to opium-like receptors [Mol. Pharmacol. 10: 868 (1974)].

Some of the substituted 7-azabicyclo [2.2.1] heptane and heptene derivatives described herein exhibit, in addition to central analgesic activity, various degrees of peripheral anti-inflammatory and peripheral analgesic activity which are useful in the medical field. A method for assaying peripheral anti-inflammatory activity is known in the art (Barber, A. and Gottschlich, R .: Opioid Agonists and Antagonists: An Evaluation of Their Peripheral Actions in Inflammation, Vol. 12, No. 5, pp. 525-526). . (September 1992)]; the tests include: increased pain in the soles of rats caused by prostaglandin E2 or carrageenan; inflammation in the knee joint of cats caused by carrageenan, bradykinin, or PGE ₂ ; formalin induced pain in mice and rats; inflammation in rats, cats, and guinea pigs caused by reverse stimulation of sensory nerves in rats, cats, and guinea pigs; seizures induced by acetic acid, phenyl benzoquinone, prostaglandin or bradykinin • »♦ · · • ·

104 sleds; and arthritis induced in rats with Freund's adjuvant.

Example 63

Evaluation of the analgesic effect test

ED ₅ o (pg / kg) values obtained by testing the analgesic activity of the compounds of the invention are summarized in Table 4; the assays were performed using the Straub tail method as described in the literature (Daly, J. et al., J. Am. Chem. Soc., 102, 830 (1980); Spande, TF et al., 1992, J. Am. Chem. Soc. 114, 3475; Li T. et al., 1993, Bioorganic and Medicinal Chemistry Letters, 3, 2769.

··· «· * 4 • ·

105

Table 4

Structure of test compounds

ED 50 QQ / kg

Notes

(gg / Kg)> 100

I-epibacidin d-epibatidin

CH ₃

<10

10,000 endo and exo isomerflLk

750

H

100V®

1000 (gg / Kg) ·· * · «* ·

- 106 -

Table 4 (continued)

Structure of test compounds

ED ₅ µg / kg

Notes

<1000

250

<1000

100-200

H ca. 50

Notes • ···

107

Table 4 (continued)

Structure of test compounds

ED50 gg / kg nch, ch ₂ ci

ca. 100 ca. 10 racemic

99% © 100

H ca. 1000

- 108 -

Example 64

Investigation of nicotinic receptor binding

The ability of 7-azabicyclo [2.2.1] heptane and heptene derivatives to bind to acetylcholine-nicotine receptors has been assayed according to methods known in the art [see Zhang X. and Nordberg A .: Arch. Pharmacol., 28, 348 (1993); Middleton RE and Cohen JB. Biochemistry, 30, 6987 (1991)], nicotine sulfate was used as the reference compound, rat cortex was used as the test substrate, and [ ³ H] -NMCI radioligand was used. The results are summarized in Table 5.

Test Compounds Test Compound Inhibition in% il

109

Table 5. Concentration of the structural structures of ··· »* 9 ·· _Λ · * · · · · ·

'M 10' '10

106

ΙΟ '' ΙΟ '' io-

102

10 ''

10 '*

· 10 "

102

10 ' ⁵

10 · 'ΙΟ *

104

103

103 <r.H J-j r

10'41 10 · '10 ·'

104

100 _x CH «NH '2 HCl

· 10 '

10 ''

10 ·

104 .CH - »*

10-'m

10 · *

· 10 '

103.9

71.3 5

R = H

R = CHj

10'41

10 ' ⁷

10 '

103

Θ1

It will be apparent to those skilled in the art that the present invention may be modified and varied based on the above description. These modifications and changes are also within the scope of the invention.

Claims (30)

An azabicyclo [2.2.1] heptane of formula (I) or -heptene derivatives and salts thereof, wherein R ¹ and R ⁴ are each independently hydrogen, alkyl, preferably CH ₃ ; alkyl hydroxy, preferably -CH ₂ OH; l-l-oxa and l-l-l tube, preferably -CH ₂ OCH ₃ ; alkylthioalkyl, preferably -CH ₂ SCH ₃ ; alkylamino, preferably -CH ₂ NH ₂ ; alkylaminoalkyl or alkylamino dialkyl, preferably -CH ₂ NH (CH ₃ ) - and -CH ₂ N (CH ₃ ) ₂ ; alkoxy, preferably -OCH ₃ ; alkoxycarbonyl, preferably methoxycarbonyl; allyl, aryl or thioalkyl, preferably -SCH ₃ ; R ³ , R ⁵ and R ⁶ are each independently hydrogen; alkyl, preferably -CH ₃ ; an alkyl hydroxy group, preferably -CH ₂ OH; alkyloxyalkyl, preferably -CH ₂ OCH ₃ ; alkylthioalkyl, preferably -CH ₂ SCH ₃ ; alkylamino, preferably -CH ₂ NH ₂ ; alkylaminoalkyl or alkylamino dialkyl, preferably -CH ₂ NH (CH ₃ ) and -CH ₂ N (CH ₃ ) ₂ ; alkoxy, preferably -OCH ₃ ; thioalkyl, preferably -SCH ₃ ; halogen, preferably chlorine or fluorine; haloalkyl, preferably -CF ₃ ; -NH ₂ , alkylamino or dialkylamino, preferably -N (CH ₃ ) ₂ and -NHCH ₃ ; cyclic dialkylamino group, preferably - 111 - amidine, cyclic amidine group, preferably also N-alkyl derivatives thereof; Η O I I N-C-alkyl, -CO ₂ H; CO ₂ -alkyl, preferably -CO ₂ CH ₃ ; -C (O) -alkyl-, preferably -C (O) CH ₃ ; -CN, -C (O) NH ₂ -C (O) NH (alkyl) -, -C (O) N (alkyl) ₂ , preferably -C (O) N (CH ₃ ) ₂ ; allyl, -SO ₂ (alkyl), -SO ₂ (aryl), preferably -SO ₂ (C ₆ H ₅ ); -S (O) alkyl, -S (O) aryl, aryl, heteroaryl; obsession R ⁵ and R ⁶ together are alkylidene or haloalkylidene, preferably -CH ₂ - and -CF ₂ -; epoxide (-O-), episulfide (-S-), imino [-N (alkyl) - or -N (H) -] or a fused aryl or heteroaryl, preferably a fused phenyl ring; 112 R ² is independently hydrogen, alkyl, preferably CH ₃ ; alkenyl, preferably -CH ₂ -HC = CH ₂ ; an alkyl hydroxy group, preferably -CH ₂ -OH; alkyloxyalkyl, preferably -CH ₂ -O- (alkyl), alkylamine, preferably -CH ₂ NH ₂ ; carboxylate, C (O) O-alkyl, preferably CO ₂ Me; C (O) O-aryl, C (O) O-heteroaryl, COO-aralkyl, -CN, Q, C (O) Q, alkyl (Q) -, alkenyl (Q), -alkynyl ( Q), -O- (Q), -SQ, -NH-Q or -N (alkyl) -Q; R ² and R ³ together are -C (O) -N (R ⁸ ) -C (O) or CH (OH) -N (R ⁸ ) -C (O) - wherein R ⁸ is alkyl or aryl preferably phenyl or heteroaryl; R ⁷ is hydrogen, alkyl, preferably CH ₃ , or -CH ₂ CH ₃ ; alkyl substituted with one or more halogen atoms, preferably -CH ₂ CH ₂ Cl; -CH ₂ - (cycloalkyl) -, preferably -CH ₂ - (cyclopropyl); -CH ₂ CH = CH ₂ , -CH ₂ CH 2 (C ₆ H 5), I ₁ H ixoxy, preferably -CH ₂ CH ₂ OH; I Ki I - amino (I Ki I) ₂ , preferably -CH ₂ CH ₂ N (CH ₃ ) ₂ ; dialkyl for alkyloxyalkyl, alkylthioalkyl, aryl, quaternary ammonium, preferably + N (CH ₃ ) ₂ , N - (R ⁹ ) N - (R ⁹ ) N - (R ⁹ ) N - (R ⁹ ) II II II II -C-H; C-alkyl; -C-aryl; C-O (alkyl); N- (R ⁹ ) N- (R ⁹ ) N- (R ⁹ ) II II II -CS- (alkyl) -CNN (R ⁹ ) ₂ -C-NHY '; I H 113 µL of lower alkyl; obsession - (CH ₂ O) _0. IPR ¹⁰ ; -PR ¹⁰ ; - (CH ₂ ) NR ⁹ -PR ¹⁰ ; - (CH ₂ ) ₀ -isS ¹⁰ ; -CH ₂ OCC (CH ₃ ) ₃ ; -CH ₂ OC-aryl; -CH ₂ OC-alkyl; wherein R ⁹ is hydrogen or alkyl; wherein Y * is CN, NO ₂ , alkyl, OH, -O-alkyl; wherein Z is oxygen or sulfur; wherein R ¹⁰ and R ¹¹ are independently -O '-OH, -O-alkyl, -Ο-aryl, -NH ₂ , -NH (alkyl), -N (alkyl) ₂ , -NH (aryl), and -N (aryl) ₂ , Q represents H, C cl cl cl 114 • · · Wherein the substituent at Q is optionally 1-3 W may carry and W is alkyl, preferably -CH ₃ ; halogen, preferably chlorine or fluorine; aryl, heteroaryl, -OH, alkoxy, preferably -OCH ₃ ; -SH, thioalkyl, preferably -SCH ₃ ; -SO (alkyl), preferably -SOCH ₃ ; -SO ₂ alkyl, preferably -SO ₂ CH ₃ ; -OCH ₂ CH = CH _2, -OCH ₂ (C ₆ H _5), CF _{3 R,} CN, alkylenedioxy group; preferably -methylenedioxy, -CO ₂ H, -CO ₂ alkyl, preferably -CO ₂ CH ₃ ; -OCH ₂ CH ₂ OH, -NO ₂ , -NH ₂ , -NH (alkyl) -, preferably -NHCH ₃ ; -N (alkyl) ₂ , preferably II 116 -N (CH ₃ ) ₂ ; - Ν Η C (O) I is I, preferably -NHC (O) CH ₃ ; -SO ₂ CF ₃ , or -NHCH ₂ aryl, preferably -NHCH ₂ (C ₆ H 5); and wherein the dashed line represents an optional double bond. Compounds according to claim 1, wherein R ⁷ is methyl, allyl, methylcyclopropyl, methylcyclobutyl, phenethyl, hydroxyethyl, methoxyethyl, methylthioethyl. , dimethylaminopropyl or (4-methoxybenzyl). Compounds according to claim 1, wherein 2-exo- (3-pyridyl); 2-endo- (3-pyridyl); 7-methyl-2-exo- (3-pyridyl); 7-cyclopropylmethyl-2-exo- (3-pyridyl); 2-exo- (6-chloro-3-pyridyl); There are 2-exo (6-fluoro-3-pyridyl) and 7-phenethyl-2-exo (3-pyridyl) groups. Compounds according to claim 1, wherein 2-exo- (4-pyridyl); 7-methyl-2-exo- (4-pyridyl); 7-allyl-2-exo- (4-pyridyl); and 7-cyclopropylmethyl-2-exo- (4-pyridyl). Compounds according to claim 1, wherein 2-exo- (3-chloro-4-pyridyl); 7-cyclopropylmethyl-2-exo- (3-chloro-4-pyridyl); and 7-phenethyl-2-exo (3-chloro-4-pyridyl). The compound of claim 1, wherein 2-exo- (2-fluoro-5-fluoride); 2-exo- (2-methoxy-5-pyridyl); 2-exo (2-methylthio-5-pyridyl); 2-exo (2-methyl-5-pyridyl); There is a 2-exo (2-dimethylamino-5-pyridyl) group and their 7-cyclopropylmethyl derivatives. The compound of claim 1, wherein the 2-position substituent is phenyl; (3-Chloro- ίί - 117-phenyl); (3-dimethylamino-phenyl); (3-trifluoromethyl-phenyl); (3,4-methylenedioxy-phenyl); (3,4-dimethoxy-phenyl); (4-fluoro-phenyl); (4-hydroxy-phenyl); (4-methylthio-phenyl); (4-methylsulfonyl-phenyl); (3,5-difluorophenyl); (Chloro-phenyl); (2-naphthyl); (7-methoxy-2-naphthyl); (5-chloro-2-methylthio-phenyl); (Chloro-5-thiazolyl) alkyl; (4-pyrimidyl) alkyl; (2-chloro-5-pyrimidyl) alkyl; (5-chloro-2-pyridazinyl) alkyl; (1,2,4-thiadiazolyl) group; (5-dimethylaminomethyl-2-furyl) alkyl; 2- (5-indolyl) alkyl; 2- (5-fluoro-3-indolyl) alkyl; 2- (5-methoxy-3-indolyl) alkyl; 2- (4-chlorobenzyl) alkyl; 2- (5-chloro-3-pyridylmethyl) alkyl; 2- (4-pyridylmethyl) alkyl; 2-nicotinyl group; 2- (6-chloro-nicotinyl) alkyl; 2-isonicotinoyl group; 2- (3-chloro-isonicotinyl) alkyl; 2- (4-chlorobenzoyl) alkyl; 2- (4-dimethylamino-benzoyl) group; 2- (3,4-dimethoxybenzoyl) alkyl; and the exo and endo isomers of these compounds, and wherein the substituent at the 7-position is hydrogen, methyl, cyclopropyl-1-methyl, allyl or phenethyl. Compounds according to claim 1, wherein R ¹ and R ⁴ are independently methyl, hydroxymethyl, methoxymethyl, methoxycarbonyl, allyl, benzyl, (4-fluorobenzyl) - or (4-methoxybenzyl). Compounds according to claim 1, wherein R ³ is methyl, hydroxymethyl, methoxymethyl, methoxycarbonyl, carboxy, carbamoyl, cyano, acetyl, aminomethyl, 118 dimethylaminomethyl, methylthiomethyl, phenylsulfonyl, methanesulfonyl, benzyl and allyl. 10. A compound according to claim 1 wherein R ^s and R ⁶ is trifluoromethyl, methoxy, methyl, methoxycarbonyl ·, hydroxymethyl, methoxymethyl, chloro or hydroxy. 11. Compounds according to claim 1, wherein a double bond is present between the carbon atoms 2 and 3. Compounds according to claim 1, wherein the carbon atoms 5 and 6 have a double bond. 13. A compound according to claim 1, wherein the substituent at the 2-position is 2-exo- (3-pyridyl), 2-exo- (6-chloro-3-pyridyl), or 2-exo- (6) fluoro-3-pyridyl); and the 7-substituent is N-phosphate and salts thereof; NH NH -C-H. —C-CH3. NH — C — isoPr NH. —C-NH ₂ , NH _CH NH —CN <—C-NHCH,. CH ₃ NH-C-NHOH NH-C-NHNH ₂ NH-C-NHNOj NH -C = N-NHC YOU --- CHjOCCtCHJj · - 119 - 14. A process for the preparation of 7-azabicyclo [2.2.1] heptane and heptene derivatives comprising (i) combining an optionally substituted pyrrole with a pentamine-osmium (II) complex and a dipolarophilic derivative. forming an azabicyclo [2.2.1] heptene-osmium complex and (ii) removing the pentamine osmium from the resulting 7-azabicyclo [2.2.1] heptene. 15. A process according to claim 14 wherein the pyrrole is 2,5-dialkylpyrrole, 2-alkylpyrrole, 3-alkylpyrrole, 1-alkylpyrrole, 3,4-dialkylpyrrole, pyrrole, 1-silylated pyrrole, (1, 2 or 3) -alkoxy or aminopyrrole, 2,3-dialkoxypyrrole, 2,5-dialkoxypyrrole or 3,4-dialkoxypyrrole are used. 16. The method of claim 14 wherein the dipolarophil is Z ¹ -C = C ^{2 2} , wherein Z ¹ and Z ² are electron withdrawing groups. 17. The process of claim 16 wherein the dipolarophil is a compound wherein Z ¹ and Z ² are independently CO (alkyl, aryl or heteroaryl), C (O) H, CO 2 (alkyl) -, aryl or heteroaryl), or SO 2 (alkyl, aryl or heteroaryl), or wherein Z ¹ and Z ² together are (CO) 2 O or (CO) ₂ NR ¹² where R ¹² is an alkyl group, preferably CH ₃ or C ₂ H ₅ ; aryl, preferably phenyl, or heteroaryl. 9 ·· » - 120 - 18. The process of claim 14 wherein the dipolarophil is 3-vinylpyridine, N-methylated or 6-carboxylated pyridyl acrylate, alkyl acrylate, alkyl methacrylate, pyridyl-substituted vinyl sulfone, acrylonitrile, anhydrides, maleic acid imides, alpha-methylene-β-butyrolactone, maleate or fumarate. 19. The process of claim 14, wherein the pentaamine osmium (II) is produced in situ by reduction of the pentaamine osmium (II), wherein the reducing agent is an electron having a reducing potential of less than -0.75 V relative to hydrogen. a reducing agent is used. 20. The process according to claim 14, wherein the anion bound to the pentaamine osmium is a CF ₃ SO ₃ ', PF ₆ ' or (alkyl or aryl) SO ₃ 'anion. 21. A process according to claim 19 wherein the reducing agent is magnesium, zinc, aluminum, sodium, lithium or cobaltocene. 22. The process of claim 19, wherein the optionally substituted pyrrole, the pentaamine-osmium (III) and the reducing agent are stirred at a temperature of 0 to 50 ° C until the desired organic metal complex is obtained. 23. The process of claim 14, wherein a functional derivative of 7-azabicyclo [2.2.1] heptene is added while forming a pentaamine-osmium complex with the π-pathway of the heptene group. · «· · ·« ·· • * « - 121 - 24. The process of claim 14, wherein the optionally substituted 7-azabicyclo [2.2.1] heptene is reduced to an optionally substituted 7-azabicyclo [2.2.1] heptane. 25. A process for the preparation of optionally substituted 7-azabicyclo [2-2.1] heptane and heptene derivatives wherein the optionally substituted pyrrole bearing an electron-withdrawing substituent on the nitrogen atom is arylsulfonyl (optionally substituted aryl or heterocyclic). (group) -acetylene. 26. A process according to claim 25 wherein the pyrrole is 3,4-di (CF ₃ ) -pyrrole, 3- (thioalkyl) pyrrole, 2,5-dialkylpyrrole, 3,4-bis (trifluoromethyl) pyrrole. methyl) pyrrole, 2-alkylpyrrole, 2-alkoxyalkylpyrrole, 2-alkylthioalkylpyrrole, 2-dialkylaminoalkylpyrrole, alkylpyrrole-2-acetate, 2-alkoxyalkoxy -alkylpyrrole, 3-aryloxyalkylpyrrole, 2-alkoxypyrrole, 3-alkoxypyrrole, 3-aryloxypyrrole, 3,4-dialkylpyrrole or 3-alkylpyrrole are used. 27. A process according to claim 25 wherein the N-electron withdrawing group is a methoxycarbonyl, benzyloxycarbonyl or tert-butoxycarbonyl group. 28. A pharmaceutical composition, wherein the composition is in an effective amount according to any one of claims 1-13. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 1, and a pharmaceutically acceptable excipient or carrier. · «· · ··· 122 ll 29. The pharmaceutical composition of claim 28, wherein the composition comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, in an amount effective to relieve pain in a mammal or to treat an inflammatory condition of a mammal. 30. The composition of claim 29, wherein the mammalian patients treated with the composition are human patients.